Modified Release Formulations Of A Bupropion Salt

ABSTRACT

The present invention relates to pharmaceutical compositions, formulations and medicaments comprising a bupropion salt, in particular, modified-release tablets comprising an effective amount of bupropion hydrobromide, and the use of the bupropion salt to prepare a medicament to treat a condition.

RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.11/751,768, filed May 22, 2007, now pending; which is a continuation ofU.S. application Ser. No. 11/475,252, filed Jun. 27, 2006, now allowed;and claims priority to U.S. Provisional Application Ser. No. 60/693,906filed Jun. 27, 2005.

FIELD OF THE INVENTION

There is a need for dosage forms comprising a pharmaceuticallyacceptable salt of bupropion that is more stable than bupropionhydrochloride. Accordingly, the present invention relates to dosageforms comprising an effective amount of a pharmaceutically acceptablesalt of bupropion that is more stable than bupropion hydrochloride. Thepresent invention also relates to the use of such dosage forms for thetreatment of one or more conditions in a subject suitable for treatmentby bupropion or pharmaceutically acceptable salts thereof such asdepression, nicotine addiction and obesity.

BACKGROUND

Bupropion is an antidepressant chemically unrelated to tricyclics,tetracyclics, selective serotonin re-uptake inhibitors (SSRIs), or otherknown antidepressant agents. The drug resembles a psycho stimulant interms of its neurochemical and behavioral profiles in vivo, but it doesnot reliably produce stimulant-like effects in humans at clinicallyprescribed doses. Its structure closely resembles that of diethylpropionand it is related to phenylethylamines. It is designated as(±)-1-(3-chlorophenyl)-2-[(1,1-dimethylethyl)amino]-1-propanonehydrochloride and by its generic name amfebutamone hydrochloride.Bupropion hydrochloride is commercially available as an immediaterelease form (WELLBUTRIN®) and a sustained release form (WELLBUTRIN® SRand ZYBAN®). Both WELLBUTRIN® SR AND ZYBAN® are chemically andpharmaceutically identical.

The neurochemical mechanism of the antidepressant effect of bupropion isnot well known. Bupropion does not inhibit monoamine oxidase. Bupropionaffects chemicals within the brain that nerves use to send messages toeach other. These chemical messengers are called neurotransmitters. Theneurotransmitters that are released by nerves are taken up again by thenerves that release them for reuse (this is referred to as reuptake).Many experts believe that depression is caused by an imbalance among theamounts of neurotransmitters that are released. It is believed thatbupropion works by inhibiting the reuptake of the neurotransmittersdopamine, serotonin, and norepinephrine, an action which results in moredopamine, serotonin, and norepinephrine made available to transmitmessages to other nerves. Accordingly, bupropion is unique in that itsmajor effect is on dopamine, an effect which is not shared by the SSRIs(e.g. paroxetine (PAXIL®), fluoxetine (PROZAC®), sertraline (ZOLOFT®))or the tricyclic antidepressants or TCAs (e.g. amitriptyline (ELAVIL®),imipramine (TOFRANIL®), desipramine (NORPRAMIN®)).

WELLBUTRIN® and WELLBUTRIN® SR are used for the management ofdepression. ZYBAN® has been approved as an aid to patients wanting toquit smoking. WELLBUTRIN®, the immediate release formulation ofbupropion, is dosed three times a day, suitably with 6 or more hours inbetween doses. For patients requiring more than 300 mg bupropion a day,each dose should not exceed 150 mg. This requires administration of thetablets at least 4 times a day with at least 4 hours in between doses.The immediate release formulation results in more than a 75% release ofthe bupropion into the dissolution media in 45 minutes, and one of themajor side effects of bupropion has been the incidence of seizures,which in part appears to be strongly associated with the immediaterelease of the bupropion into the system. Accordingly, sustained releaseproducts were developed to avoid the incidence of seizures. Thesustained release products are dosed twice daily.

In general, patient compliance is a problem with medications thatrequire a multiple dosing regimen and is especially problematic withdepressed individuals. While sustained release formulations havesimplified the dosing regimen and increased patient compliance, there isstill room for further simplifying the dosing regimen and furtherimproving patient adherence to the dosing regimen. The development of anapproved stable once daily modified-release bupropion formulation wouldbe an advance in the art.

The selection of a suitable salt for a drug candidate is recognized asan important step in the preclinical phase of drug development; however,the scientific literature on this topic is rather limited. Changing thesalt form of a drug is a recognized means of modifying its chemical andbiological properties without modifying its structure. As yet, there isno reliable way of predicting exactly what effect changing the salt formof an active drug will have on its biological activity. A decision tochange the salt form at a later stage introduces the need to repeattoxicological, formulation and stability tests, with obviousimplications for the overall development and production time for the newpharmaceutical product.

In general, a few of the factors that should be considered during a saltselection include: What is the effect of the salt on the chemicalstability of the drug substance and the drug product? Does the salt forma hydrate? What is the solubility of the salt and is it appropriate forin vivo administration? What is the quality of the salt with regard toprocessing, issues with scale up, safety, etc.?

According to the CHEMICAL ABSTRACTS REGISTRY® Database, the only saltsof bupropion that have been previously reported are the hydrochloride(HCl), (2Z)-2-butenedioate, (2E)-2-butenedioate, methane sulfonate,formic acid, 2-hydroxy-1,2,3-propanetricarboxylate, phosphate andtrifluoromethanesulfonate salts.

There is a need for a once daily formulation of a pharmaceuticallyacceptable salt of bupropion with enhanced stability.

SUMMARY

The present invention relates to dosage forms comprising an effectiveamount of a pharmaceutically acceptable salt of bupropion (bupropionhydrobromide) which is more stable than bupropion hydrochloride. Inparticular such bupropion compositions are more stable than otherwiseequivalent bupropion hydrochloride compositions when stored for at least3 months and/or at least 6 months at 40 degrees C. and 75% relativehumidity (“accelerated storage conditions”) as evidenced by a reducedamount of at least one moiety characteristic of bupropion degradationand/or exhibit less fluctuation or reduction in potency after beingstored for at least 3 months and/or at least 6 months under acceleratedstorage conditions relative to an otherwise similar bupropionhydrochloride composition as evidenced e.g., by less fluctuation in thein vitro dissolution profile in at least one dissolution medium over a24 hour period.

The present invention also relates to the use of such more stablebupropion hydrobromide dosage forms for the treatment of one or moreconditions in a subject.

The dosage forms of the present invention comprise a compound of formulaI (bupropion hydrobromide):

and pharmaceutically acceptable carriers, excipients and/or diluents,said composition having greater stability than a correspondingpharmaceutical composition comprising bupropion hydrochloride andpharmaceutically acceptable carriers, excipients and/or diluents.

In other embodiments of the present invention, the bupropion salt can bein the form of its anhydrous, hydrated, and solvated forms, in the formof prodrugs, and in the individually optically active enantiomers of thebupropion salt, such as for example (+)-bupropion and (−)-bupropion.Suitable pharmaceutically acceptable salts of bupropion for use in thepresent invention are more stable than bupropion hydrochloride. Suitablesalts of bupropion also include for example, pharmaceutically acceptableacid addition salts. In certain embodiments, the acid addition salt ofbupropion can be indirectly obtained by the separate addition ofbupropion and an acid to the core formulation.

Another embodiment of the present invention contemplates the use ofbupropion hydrobromide to prepare a medicament to treat a conditionwhich can benefit from administration of bupropion, wherein saidmedicament has greater stability than a corresponding medicamentcomprising bupropion hydrochloride. Herein enhanced stability means thatthe salt or a composition containing is more stable after being storedfor at least 3 months and/or 6 months at 40 degrees C. and 75% relativehumidity (accelerated storage conditions) as evidenced by a lesseramount of at least one moiety characteristic of bupropion degradationand/or a reduction or fluctuation in potency evidenced e.g., by agreater fluctuation in the in vitro dissolution profile over at least a12 or a 24 hour period in at least one dissolution medium relative andunder the same conditions to an otherwise equivalent bupropionhydrobromide composition stored for the same length of time under thesame accelerated storage conditions.

As discussed infra and generally known in the art appropriatedissolution medium and appropriate conditions for assaying thedissolution characteristics of pharmaceutical dosage forms such astablets are well known in the art and are contained in the United StatesPharmacopoiea and its European or Japanese counterparts and include byway of example dissolution in USP Type 1 apparatus (Rotating BasketMethod) in 900 ml water; 0.1 N HCl; 0.1N HCl+0.1% Cetrimide; USP bufferpH 1.5; Acetate buffer pH 4.5; Phosphate Buffer pH 6.5; or PhosphateBuffer pH 7.4 at 75 RPM at 37 degrees C+/−0.5 degrees C.

Additionally, other dissolution media include USP-3 media and USP-3dissolution conditions i.e., SGF pH 1.2; Acetate buffer pH 4.5 andPhosphate Buffer pH 6.8.

In another embodiment of the present invention, the dosage formscomprising bupropion hydrobromide can be used to treat a condition whichcan benefit from administration of bupropion such as depression,seasonal effective disorder, smoking cessation or obesity.

Another embodiment of the present invention contemplates the use ofbupropion hydrobromide to prepare a modified-release tablet of bupropionhydrobromide with enhanced stability. The tablets of the presentinvention, comprising bupropion hydrobromide, have unexpected enhancedstability compared to the prior art bupropion hydrochloride tablets.

In another embodiment the present invention contemplates the use ofbupropion hydrobromide to produce once-daily administrable tablets orother dosage forms that are bioequivalent to WELBUTRIN™ orZYBAN/WELLBUTRIN™ SR tablets as defined by FDA criteria whenadministered once daily to a subject in need thereof. In particular atleast one of the Tmax, Cmax, and AUC profile are within 80-125% ofWELLBUTRIN™—and ZYBAN™/WELLBUTRIN™ when administered once daily to asubject in need thereof. Preferably, these formulations also will befree of any significant food effect.

In addition the present invention provides bupropion hydrobromide dosageforms containing at least one coating, e.g., tablets, which areresistant to dose dumping in high alcohol, e.g., 40% ethanol, because ofthe presence of an appropriate coating, i.e., a SMARTCOAT.™

Another embodiment of the present invention further contemplates amethod of preparing a medicament for the treatment of a condition whichcan benefit from the administration of bupropion comprising bringing aneffective amount of bupropion hydrobromide into contact with one or morepharmaceutically acceptable carriers, diluents and/or excipients.

Another embodiment of the present invention contemplates a method oftreating a condition which can benefit from the administration ofbupropion comprising administering an effective amount of bupropionhydrobromide to a subject. For example, such conditions which canbenefit from administration of bupropion hydrobromide include but arenot limited to depression, including seasonal effective disorder,cognitive symptoms in depression, bipolar depression, post partumdepression, minor depression, lack of energy in depression, suicidaldepression, anxiety disorders, generalized anxiety disorder, socialanxiety disorder, obsessive compulsive disorder, post traumatic stressdisorder (PTSD), panic disorder, disorders requiring a stimulant effect,attention deficit/hyperactivity disorder (ADHD), narcolepsy,hypersomnia, substance-abuse disorders, stimulant dependence, marijuanadependence, nicotine dependence, obesity, female and male sexualdysfunction such as premature ejaculation, premenstrual syndrome,premenstrual dysphoric disorder, neuropathic pain, fibromyalgia,diabetic neuropathy, viral infection, sleep apnea, sleep disorders andmigraines. The conditions may be focused on different demographicpopulations, such as reproductive related mood disorders, specific agepopulation disorders and specific ethnic population disorders.

According to an aspect of the invention, there is provided a compositionfor administration to a subject in need of treatment for a condition.The composition comprises a pharmaceutically effective amount of abupropion salt that is more stable than bupropion hydrochloride asdefined herein. In addition, the composition is more stable than acorresponding composition comprising bupropion hydrochloride.

The present invention includes both oral and non-oral bupropionhydrobromide containing medicaments. Prior to the present inventionmedicaments containing bupropion hydrobromide were unavailableParticularly, the invention embraces compositions suitable for topical,injectable, inhalation and other modes of administration. Typically themedicaments of the present invention are orally administrable.

In particular the invention includes extended release formulations. Inanother aspect, the present invention includes delayed releaseformulations. Further, the present invention embraces enhancedabsorption formulations.

In a particular embodiment, the inventive compositions includecontrolled release matrix tablet formulations.

In a more particular implementation of the invention, a bupropionmedicament composition according to the invention may comprise (i) acore that includes bupropion hydrobromide, a binder and a lubricant; and(ii) a control releasing coat substantially surrounding said core;wherein said composition provides controlled release of said bupropionhydrobromide. Such composition optionally may comprise one or moreadditional coatings surrounding the core and/or the control releasingcoat such as moisture barrier coats, enteric coats or coatings thataffect the physical integrity and/or appearance of the bupropion Thebinder can be selected from known pharmaceutical binders such aspolyvinyl alcohol. The lubricant also can be selected from knownpharmaceutical lubricants such as glyceryl behenate. The controlreleasing coat can include a water-insoluble polymer, a water-solublcpolymer, and optionally a plasticizer. The water-insoluble polymer canbe selected from a range of water insoluble polymers useful in extendedrelease pharmaceutical compositions such as ethylcellulose. Thewater-soluble polymer can be selected from a variety of water-solublepolymers useful in extended release pharmaceutical compositions such aspolyvinylpyrrolidone. The plasticizer if present can be selected from arange of known plasticizers such as mixtures of polyethylene glycol 4000and dibutyl sebacate. These compositions include once-dailyadministrable compositions that are bioequivalent to WELLBUTRIN™ orZYBAN™/WELLBUTRIN™ SR tablets when administered once-daily to a subjectin need thereof, may be bioequivalent. These compositions optionally maynot exhibit a food effect and/or may be resistant to dose dumping in thepresence of high alcohol concentrations (i.e., 40% by weight ofethanol).

In a more particular implementation of the invention, the subjectbupropion composition comprises (i) a core that includes bupropionhydrobromide, a binder and a lubricant; and (ii) a control releasingcoat substantially surrounding said core; wherein said control releasingcoat includes an aqueous dispersion of a neutral ester copolymer withoutany functional groups, a polyglycol having a melting point greater than55° C., and one or more pharmaceutically acceptable excipients, whereinsaid coat is coated onto said core and cured at a temperature at leastequal to or greater than the melting point of the polyglycol.Optionally, this medicament may comprise one or more additional coatingssurrounding the core and/or control-release coating such as moisturebarrier coats, enteric coats, coats that preclude dose dumping inspecific media such as alcohol, and coatings that affect the physicalstability or integrity of the medicament and/or its physical appearance.

In a particular implementation of the invention, the subject bupropioncomposition comprises multiparticulates.

In a particular implementation of the invention, the subject bupropioncomposition comprises a second drug. The second drug can be any drugwhich may be administered in combination with the subject bupropion saltsuch as other anti-depressants, SSRI's, anti-anxiety agents, etc. Theinvention embraces drug combinations wherein the second drug may elicita synergistic benefit on bupropion efficacy as well as non-synergisticdrug combinations. In particular the invention embraces bupropionhydrobromide compositions wherein the second drug is citalopram,escitalopram and/or venlafaxine.

According to another aspect of the invention, there is provided a methodof using a composition according to any of the foregoing claims fortreatment in a subject in need of such administration. This includes inparticular the treatment of depression, obesity and abuse disorders suchas nicotine addiction and smoking cessation. In an exemplary embodimentssuch treatments comprise once-daily dosage regimens.

According to another aspect of the invention, there is provided a use ofbupropion hydrobromide to prepare a medicament to treat conditions whichbenefit from administration of bupropion, wherein said medicament hasgreater stability than a corresponding medicament comprising bupropionhydrochloride.

In accordance with one aspect of the present invention, there isprovided a controlled release tablet, comprising (i) a core comprisingan effective amount of a bupropion hydrobromide, a binder, a lubricant;and (ii) a control-releasing coat surrounding said core; and optionally(iii) a moisture barrier surrounding said control-releasing coat or thecore; and; wherein the extended release tablet exhibits a dissolutionprofile such that after 2 hours, no more than 20% of the bupropionhydrobromide content is released, for example in certain embodiments 2%to 18%, 4% to 8%, or 5% of the bupropion hydrobromide content isreleased after 2 hours; after 4 hours, 15% to 45% of the bupropionhydrobromide content is released, for example in certain embodiments 21%to 37%, 28% to 34%, or 32% of the bupropion hydrobromide content isreleased after 4 hours; after 8 hours, 40% to 90% of the bupropionhydrobromide content is released, for example in certain embodiments 60%to 85%, 68% to 74%, or 74% of the bupropion hydrobromide content isreleased after 8 hours; and after 16 hours no less than 80% of thebupropion hydrobromide content is released, for example in certainembodiments not less than 93%, not less than 96%, or not less than 99%of the bupropion hydrobromide content is released after 16 hours; andwherein the bupropion hydrobromide salt contained in said extendedrelease tablet has greater stability than a tablet having the samecomposition with the exception that bupropion hydrobromide is replacedwith bupropion hydrochloride.

In another aspect the composition exhibits a dissolution profile suchthat after 2 hours not more than 40% of the bupropion hydrobromide isreleased, e.g., 33%, after 4 hours from 40-75%, e.g., 59% of thebupropion hydrobromide is released, after 8 hours not less than 75% ofthe bupropion hydrobromide is released, e.g., 91%, and after 16 hoursnot less than 85% of the bupropion hydrobromide is released, e.g., 97%.These medicaments will typically comprise 50-500 mg of bupropionhydrobromide. In exemplary embodiments disclosed herein the medicamentcontain 174 mg or 348 mg of bupropion hydrobromide.

In accordance with another aspect of the present invention, there isprovided an enhanced-absorption tablet, comprising (i) a core comprisingan effective amount of bupropion hydrobromide, a binder, a lubricant;and (ii) a control-releasing coat surrounding said core; and wherein theenhanced absorption tablet exhibits a dissolution profile such thatafter 2 hours, no more than 25% of the bupropion hydrobromide content isreleased, for example in certain embodiments 10% to 20% of the bupropionhydrobromide content is released after 2 hours; after 4 hours, 25% to55% of the bupropion hydrobromide content is released, for example incertain embodiments 30% to 50%, of the bupropion hydrobromide content isreleased after 4 hours; after 8 hours, more than 60% of the bupropionhydrobromide content is released, for example in certain embodiments 70%to 90% of the bupropion hydrobromide content is released after 8 hours;and after 16 hours more than 70% of the bupropion hydrobromide contentis released, for example in certain embodiments more than 80% of thebupropion hydrobromide content is released after 16 hours; and whereinsaid extended release tablet has greater stability than a tablet havingthe same composition with the exception that bupropion hydrobromide isreplaced with bupropion hydrochloride. This composition optionally mayfurther comprise one or more additional coats surrounding the coreand/or control-release coat.

In an exemplary embodiment this composition may comprise a dissolutionprofile such that after 2 hours not more than 40% of bupropionhydrobromide is released therefrom, e.g., 33%; after 4 hours 40-75% ofbupropion hydrobromide is released therefrom, e.g., 59%, after 8 hoursnot less than 75% of bupropion hydrobromide is released therefrom, e.g.,91%, and after 16 hours not less than 85% of bupropion hydrobromide isreleased therefrom, e.g., 97%.

In accordance with a further aspect of the invention there is provided asalt of bupropion and polymorphic forms thereof having enhancedstability wherein the salt is hydrobromide, and wherein enhancedstability refers to the reduced formation of at least one degradationproduct characteristic of bupropion degradation and/or the increasedretention of potency as evidenced e.g., by a reduced fluctuation in thein vitro dissolution profile in at least one dissolution medium relativeto an otherwise equivalent formulation containing bupropionhydrochloride when the formulations containing these bupropion salts arestored for prolonged time periods under equivalent conditions. Inparticular enhanced stability refers to bupropion hydrobromidecompositions that are less subject to degradation than an otherwiseequivalent bupropion hydrochloride composition when stored underaccelerated storage conditions, i.e., 40 degrees C. at 75% relativehumidity for at least 3 months, and/or for at least 6 months or longerand/or which exhibits less fluctuation or reduction in potency asevidence by a reduced fluctuation in the in vitro dissolution profile inat least one dissolution medium wherein dissolution is effected underthe same conditions after the bupropion hydrobromide and bupropionhydrochloride compositions are stored for at least 3 months and/or atleast 6 months at 40 degrees C. and 75% relative humidity. In thepresent invention, as described infra, degradation is assayed based onthe amount of at least one compound characteristic of bupropiondegration.

More particularly, the present invention embraces enhanced absorptiontablets comprising (i) a core comprising an effective amount ofbupropion HBr, a binder, a lubricant: and (ii) a control-releasing coatsurrounding said core; wherein the enhanced absorption tablet exhibits adissolution profile such that after 2 hours no more than 40% bupropionis released, (e.g, 33%); after 4 hours 40-75% bupropion is released(e.g., 59%), after 8 hours at least 75% is released (e.g., 91%); andafter 16 hours at least 85% is released (e.g, 97%)

As discussed infra, in vitro dissolution of bupropion from controlled orextended release formulations according to the invention can bedetermined by methods well known to those skilled in the pharmaceuticalart. Suitable methods are contained in the United States Pharmacopoiea(USP) as well as European and Japanese counterparts of the USP and areexemplified infra. This includes by way of example effecting dissolutionin a USP 1 apparatus (Rotating Type Basket Method) in 900 ml water, 0.1NHCl, 0.1N HCl+0.1% Cetrimide, USP Buffer pH 1.5, Acetate Buffer pH 6.5or Phosphate Buffer pH 7.4 at 75 RPM at 37 degrees C+/−0.5 degrees C. orby effecting dissolution using a USP3 dissolution medium such as SGFhaving a pH 1.2; acetate buffer having a pH of 4.5 or phosphate bufferhaving a pH of 6.8.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows a DVS profile for bupropion hydrobromide (HBr).

FIG. 2 shows DVS isotherm data for bupropion HBr.

FIG. 3 is a bar graph showing the results of stability testing on thebupropion salts mixed with excipients in closed vials over 20 days at40° C./75% relative humidity (RH).

FIG. 4 is a bar graph showing the potency of the bupropion salts mixedwith excipients after storage in closed vials over 20 days at 40° C./75%RH compared to their initial potency.

FIG. 5 is a bar graph showing the potency of the bupropion salts mixedwith excipients and water after storage in closed vials over 32 days at40° C. compared to their initial potency.

FIG. 6 is a bar graph showing the potency of the bupropion salts mixedwith excipients, water, isopropyl alcohol and ethanol after storage inclosed vials over 32 days at 40° C. compared to their initial potency.

FIG. 7 is a bar graph showing the potency of the bupropion salts mixedwith excipients, isopropyl alcohol and ethanol after storage in closedvials over 32 days at 40° C. compared to their initial potency.

FIG. 8 is a bar graph showing the % impurities for the bupropion saltsmixed with excipients and treated for 32 days in closed vials and spikedwith water.

FIG. 9 is a bar graph showing the % impurities for the bupropion saltsmixed with excipients and treated for 32 days in closed vials and spikedwith water, isopropyl alcohol (IPA) and ethanol (EtOH).

FIG. 10 is a bar graph showing the % impurities for the bupropion saltsmixed with excipients and treated for 32 days in closed vials and spikedwith isopropyl alcohol (IPA) and ethanol (EtOH).

FIG. 11 is a flow chart showing the overall process for the developmentof bupropion HBr XL tablets.

FIG. 12 is a flow chart demonstrating the granulation process of thebupropion HBr XL and EA tablets.

FIG. 13 is a flow chart showing the overall tabletting process ofbupropion HBr XL.

FIG. 14 is a flow chart showing the overall coating process of bupropionHBr XL.

FIG. 15 is a dissolution profile of the 4 kp, 6-7 kp and 9-10 kptablets, comparing the effects of hardness on dissolution in the studyon Batch BUP-HBr-XL-009-5.

FIG. 16 is a dissolution profile of the 348 mg Bupropion HBr cores whichhave been compressed using 9 mm tooling in the study on BatchBUP-HBr-XL-009-5.

FIG. 17 is a dissolution profile of the 348 mg Bupropion HBr cores whichhave been compressed using 10 mm tooling in the study on BatchBUP-HBr-XL-009-5.

FIG. 18 is a dissolution profile comparison of the 9 mm and 10 mmdiameter 348 mg Bupropion HBr cores in the study on BatchBUP-HBr-XL-009-5.

FIG. 19 is a dissolution profile of the 174 mg in the study on BatchBUP-HBr-XL-021-5.

FIG. 20 is a dissolution profile of BUP-HBr-XL-348 mg-013-5 (28 mg, 30mg, 32 mg and 34 mg weight gains).

FIG. 21 is a dissolution profile of BUP-HBr-XL-348 mg-013-5 (5 mg, 6 mg,and 7 mg weight gains).

FIG. 22 is a dissolution profile of BUP-HBr-XL-348 mg-018-5 (26 mg, 28mg, 30 mg and 32 mg weight gains).

FIG. 23 is a dissolution profile of BUP-HBr-XL-348 mg-018-5 (7 mg weightgain).

FIG. 24 is a dissolution profile of BUP-HBr-XL-174 mg-022-5 (22 mg, 24mg, 28 mg and 30 mg weight gains).

FIG. 25 is a dissolution profile of BUP-HBr-XL-174 mg-022-5 (5 mg, 6 mg,and 7 mg weight gains).

FIG. 26 is a dissolution profile of BUP-HBr-XL-348 mg-023-5 (26 mg, 28mg, 30 mg and 32 mg weight gains).

FIG. 27 is a dissolution profile of BUP-HBr-XL-348 mg-025-5 (26 mg, 28mg, 30 mg, and 32 mg weight gains).

FIG. 28 is a dissolution profile of BUP-HBr-XL-348 mg-025-5 (5 mg, 6 mg,and 7 mg weight gains).

FIG. 29 is a dissolution profile of BUP-HBr-XL-348 mg-026-5 (26 mg, 28mg, 30 mg, and 32 mg weight gains).

FIG. 30 is a dissolution profile of BUP-HBr-XL-174 mg-027-5 (22 mg, 24mg, and 26 mg weight gains).

FIG. 31 is a dissolution profile of BUP-HBr-XL-174 mg-027-5 (4 mg, 5 mg,6 mg, and 7 mg weight gains).

FIG. 32 is a flow chart showing the overall process for the developmentof bupropion HBr EA tablets.

FIG. 33 is a flow chart demonstrating the granulation process of thebupropion HBr EA tablets.

FIG. 34 is a flow chart showing the compression process of the 300 mgand 150 mg bupropion HBr EA Tablets.

FIG. 35 is a flow chart showing the coating process of 150 mg and 300 mgbupropion HBr EA Tablets with an ETHOCEL™ Coating.

FIG. 36 is a dissolution profile of the of tablet cores at differenthardness levels (4 kp, 6-7 kp and 9 kp) in the study on BatchBUP-HBr-XL-016-5.

FIG. 37 is a dissolution profile of the 300 mg Bupropion HBr EACores inthe study on Batch BUP-HBr-XL-016-5.

FIG. 38 is a dissolution profile of the 150 mg Bupropion HBr Cores inthe study on Batch BUP-HBr-XL-016-5.

FIG. 39 is a dissolution profile of BUP-HBr-EA-300 mg-001-5 (44 mg, 46mg, 48 mg, 50 mg 52 mg, and 54 mg weight gains).

FIG. 40 is a comparative USP3 dissolution profile of Bupropion HBr 300mg EA Tablets with 52 mg weight gain to the in vivo and the in vitroprofiles of the target (Bupropion HCl 300 mg).

FIG. 41 is a dissolution profile of BUP-HBr-EA-150 mg-002-5 (18 mg, 20mg, 22 mg, 24 mg, 26 mg, 28 mg, 30 mg, 32 mg, 34 mg and 36 mg weightgains).

FIG. 42 is a dissolution profile of BUP-HBr-EA-300 mg-003-5 (44 mg, 46mg, 48 mg, 50 mg, 52 mg, and 54 mg weight gains).

FIG. 43 is a dissolution profile of BUP-HBr-EA-300 mg-004-5 (44 mg, 46mg, 48 mg, 50 mg, 52 mg, and 54 mg weight gains).

FIG. 44 is a dissolution profile of BUP-HBr-EA-300 mg-005-5 (44 mg, 46mg, 48 mg, 50 mg, 52 mg, and 54 mg weight gains).

FIG. 45 is a dissolution profile of BUP-HBr-EA-150 mg-006-5 (24 mg, 28mg, 32 mg, 34 mg and 36 mg weight gains).

FIG. 46 is a comparative USP3 dissolution profile of bupropion HBr 150mg EA Tablets with 24 and 34 mg weight gains to the in vivo and the invitro profiles of the target (bupropion HCl 300 mg).

FIG. 47 is a bar graph showing the % impurities for the bupropion HCl XL300 mg and bupropion HBr 348 mg EC coated tablets at 40° C. and 75%relative humidity.

FIG. 48 is a bar graph showing the % impurities for the bupropion HCl300 mg (Wellbutrin XL) and bupropion HBr 348 mg XL final tablets at 40°C. and 75% relative humidity.

FIGS. 49A and 49B contain bar graphs showing the % of 3-CBA formed inforced degradation studies of bupropion hydrochloride (HCl) vs.bupropion HBr in the presence of excipients.

FIGS. 50A and 50B contain bar graphs showing the % of 852U77 formed inforced degradation studies of bupropion HCl vs. bupropion HBr in thepresence of excipients.

FIGS. 51A and 51B contain bar graphs showing the % of 20U78 formed inforced degradation studies of bupropion HCl vs. bupropion HBr in thepresence of excipients.

FIGS. 52A and 52B contain bar graphs showing the % of 827U76 formed inforced degradation studies of bupropion HCl vs. bupropion HBr in thepresence of excipients.

FIG. 53 is a graph showing the loss of API in a thermal gravimetricanalysis (TGA) experiment at 100° C. of bupropion HCl vs. bupropion HBr.

FIG. 54 is a graph showing the relative powder X-ray diffraction (PXRD)for bupropion hydrobromide polymorphic form I.

FIG. 55 is a graph showing the differential scanning calorimetry (DSC)profile of bupropion hydrobromide polymorphic form I.

FIG. 56 is a graph showing the relative PXRD for bupropion hydrobromidepolymorphic form II.

FIG. 57 is a graph showing the DSC profile of bupropion hydrobromidepolymorphic form II.

FIG. 58 is a graph showing the relative PXRD for bupropion hydrobromidepolymorphic form III.

FIG. 59 is a graph showing the DSC profile of bupropion hydrobromidepolymorphic form III.

FIG. 60 is a graph of the relative PXRD of a sample of bupropionhydrobromide polymorphic form I after 6 months under the ICH(International Conference on Harmonisation of Technical Requirements forRegistration of Pharmaceuticals for Human Use) conditions (40° C., 75%R.H.).

FIG. 61 is a graph of the PXRD of a sample of bupropion hydrobromidepolymorphic form II after 1 month under ICH conditions (40° C., 75%R.H.).

FIG. 62 is a graph of the PXRD of a sample of bupropion hydrobromidepolymorphic form III after 1 month under ICH conditions (40° C., 75%R.H.).

FIG. 63 contains the results of stability studies for Bupropion HBr XL174 mg core (Lot #Bup-HBr-XL-004-5 core; Bupropion HBr XL 348 mg core(Lot #Bup-HBr-XL-009-5 core; Bupropion HCl XL 150 mg core (Lot #05E056)and Bupropion HCl XL 300 mg core (Lot #05D380) initially, after 10 daysopen and closed, and after 20 days open and closed. The % of impurities3-CBZ, 852U77, 20U78dilu, 827U76 are shown therein.

FIGS. 64A and 64B and FIGS. 65A and 65B respectively contain stabilitydata for bupropion 348 mg HBr XL tablets (Lot #Bup-HBr-XL-348-025-5) andBupropion HBr EA 300 mg tablets (Lot #Bup-HBr-EA-300-001-5) initiallyand after 3 months, 6 months, 9 months and 12 months under acceleratedstorage conditions (40 degrees C. and 75% relative humidity). The assaytested for amount of impurities 3-CBA, 852U77, 20U78/diluent, 827U76,and also compared the dissolution profiles and appearance thereof.

FIGS. 66A and 66B compare the dissolution profiles and in vitro drugrelease of Bupropion HBr XL 348 mg tablets (final) Lot#Bup-HBr-XL-012-5, Wellbutrin XL 300 mg tablets final (Lot #05A116),Bupropion HBr XL 348 mg tablets ECl) Lot #Bup-HBr-XL-012-5 (EC 32 mgwg), and Wellbutrin XL 300 mg tablets (ECl) (Lot #05D047) in differentUSP-3 media (SGF pH 1.2, Acetate Buffer pH 4.5, and Phosphate Buffer pH6.8 over a period of 16 hours.

FIGS. 67A, 67B and 67C compare the dissolution profiles and drug releasefor Bupropion HBr 348 mg Lot #05E304 in different USP-3 media (SGF pH1.2, Acetate Buffer pH 4.5, Phosphate Buffer SIF pH 6.8) over a periodof 16 hours and further compares this release profile against therelease profile for Bup 300 XL Target (01L238) in vivo and BUP 300XLTarget (01L238) in vitro in USP-3 media.

FIGS. 68A and 68B contain comparative dissolution profiles for BupropionHBr XL 348 mg and Wellbutrin XL (final and EC) in USP-3 media (pH 1.2SGF, pH 4.5 acetate buffer and pH 6.8 phosphate buffer over a period of16 hours.

DEFINITIONS

The term “bupropion salt” herein has its ordinary meaning and includesany salt of bupropion.

The term “bupropion salt that is more stable than bupropionhydrochloride” refers to a bupropion salt or a composition containingthat is less subject to degradation than an otherwise equivalentbupropion hydrochloride salt or composition containing when stored forat least 3 months, 4 months, 5 months, and/or at least 6 months underaccelerated storage conditions (40 degrees C., and 75% relativehumidity), and/or when stored for at least 3, 4, 5 and/or 6 months underaccelerated storage conditions (40 degrees C. and 75% relative humidity)and/or which exhibits less of a reduction or fluctuation in potency asevidenced by less fluctuation in the in vitro dissolution profile in atleast one dissolution medium relative to an otherwise similar bupropionhydrochloride composition wherein dissolution is effected under the sameconditions after these compositions are stored for at least 3, 4, 5, or6 months at 40 degrees C. at 75% relative humidity. Particularly,bupropion hydrobromide salts and polymorphs thereof may result inbupropion formulations that exhibit dissolution profiles over time thatare less subject to fluctuation when stored under accelerated storageconditions for prolonged time periods, i.e., at least 3, 4, 5, or 6months at 40 degrees C. and 75% relative humidity.

The term “active”, “active agent”, “active pharmaceutical agent”,“active drug” or “drug” as used herein means any active pharmaceuticalingredient (“API”), including its pharmaceutically acceptable salts(e.g. the hydrochloride salts, the hydrobromide salts, the hydroiodidesalts, and the saccharinate salts), as well as in the anhydrous,hydrated, and solvated forms, in the form of prodrugs, and in theindividually optically active enantiomers of the API as well aspolymorphs of the API.

The term “dose dumping” herein refers to the rapid release of a drugfrom a medicament under certain conditions such as solvent conditionse.g., high (40%) ethanol.

The term “other drug” or “second drug” as used herein means a drug otherthan bupropion, including but not limited to anti-depression agents,other neuropsychiatric drugs, vasodilators, anti-anxiety agents,appetite modulators, sleep modulating drugs, SSRIs, anti-viral agents,anti-pain agents, anti-migraine agents, anti-inflammatories (bothsteroidal and non-steroidal) and more particularly may includecitalopram, escitalopram, venlafaxine, clozapine, melperone, amperozide,iloperidone, risperidone, quetiapene, olanzapine, ziprasidone,aripiprazole, reboxetine, VIAGRA®, sertraline, paroxetine, fluoxetine,gabapentin, valproic acid, amitriptyline, lofepramine, fluvoxamine,imipramine, mirtazapine, nefazodone, nortriptyline, SAM-E, combinationsthereof, and their pharmaceutically acceptable salts (e.g. thehydrochloride salts, the hydrobromide salts, the hydroiodide salts, andthe saccharinate salts), as well as in the anhydrous, hydrated, andsolvated forms, in the form of prodrugs, and in the individuallyoptically active enantiomers of the drug.

The term “formulation” or “composition” as used herein refers to thedrug in combination with pharmaceutically acceptable carriers andadditional inert ingredients. This includes orally administrableformulations as well as formulations administrable by other means.

The term “dosage form” as used herein is defined to mean apharmaceutical preparation in which doses of active drug are included.

“Modified release dosage forms” as used herein is as defined by theUnited States Pharmacopoeia (USP) as those whose drug releasecharacteristics of time course and/or location are chosen to accomplishtherapeutic or convenience objectives not offered by conventional,immediate release or uncoated normal matrix dosage forms. The rate ofrelease of the active drug from a modified release dosage form iscontrolled by features of the dosage form and/or in combination withphysiologic or environmental conditions rather than by physiologic orenvironmental conditions alone. The modified release dosage forms of theinvention can be contrasted to conventional, immediate release, oruncoated normal matrix dosage forms which typically produce largemaximum/minimum plasma drug concentrations (Cmax/Cmin) due to rapidabsorption of the drug into the body (i.e., in vivo, relative to thedrug's therapeutic index; i.e., the ratio of the maximum drugconcentration needed to produce and maintain a desirable pharmacologicalresponse). In conventional, immediate release or uncoated normal matrixdosage forms, the drug content is released into the gastrointestinaltract within a short period of time, and plasma drug levels peak shortlyafter dosing. The design of conventional, immediate release or uncoatednormal matrix dosage forms is generally based on getting the fastestpossible rate of drug release, and therefore absorbed, often at the riskof creating undesirable dose related side effects. The modified releasedosage forms of the invention, on the other hand, improve thetherapeutic value of the active drug by reducing the ratio of themaximum/minimum plasma drug concentration (Cmax/Cmin) while maintainingdrug plasma levels within the therapeutic window. The modified releasedosage forms of the invention attempt to deliver therapeuticallyeffective amount of bupropion salt and combinations thereof as aonce-daily dose so that the ratio Cmax/Cmin in the plasma at steadystate is less than the therapeutic index, and to maintain drug levels atconstant effective levels to provide a therapeutic benefit over a24-hour period. The modified release dosage forms of the invention,therefore, avoid large peak-to-trough fluctuations normally seen withconventional or immediate release dosage forms and can provide asubstantially flat serum concentration curve throughout the therapeuticperiod. Modified-release dosage forms can be designed to provide a quickincrease in the plasma concentration of the bupropion salt which remainssubstantially constant within the therapeutic range of bupropion saltfor at least a 24-hour period. Alternatively, modified-release dosageforms can be designed to provide a quick increase in the plasmaconcentration of the bupropion salt, which although may not remainconstant, declines at rate such that the plasma concentration remainswithin the therapeutic range for at least a 12 hour and desirably atleast a 24-hour period.

The modified release dosage forms of the invention can be constructed inmany forms known to one of ordinary skill in the drug delivery arts anddescribed in the prior art such as for example, “modified release matrixdosage forms”, “normal release matrix dosage forms” coated with at leastone “control-releasing coat”, “osmotic dosage forms”, “multiparticulatedosage forms”, and “gastric retention dosage forms”. The USP considersthat the terms controlled release, prolonged release and sustainedrelease are interchangeable. Accordingly, the terms “modified-release”,controlled-release”, “control-releasing”, “rate-controlled release”,“prolonged-release”, and “sustained-release” are used interchangeablyherein. For the discussion herein, the definition of the term“modified-release” encompasses the scope of the definitions for theterms “extended release”, “enhanced-absorption”, “controlled release”,and “delayed release”.

“Controlled release dosage forms” or “control-releasing dosage forms”,or dosage forms which exhibit a “controlled release” of the bupropionsalt as used herein is defined to mean dosage forms administered once-or twice-daily that release the bupropion salt at a controlled rate andprovide plasma concentrations of the bupropion salt that remaincontrolled with time within the therapeutic range of the bupropion saltover a 12 or 24-hour period. “Controlled release” or “control releasing”is defined to mean release of the drug gradually or in a controlledmanner per unit time. For example, the controlled rate can be a constantrate providing plasma concentrations of the bupropion salt that remaininvariant with time within the therapeutic range of the bupropion saltover at least a 12 or 24-hour period.

“Sustained-release dosage forms” or dosage forms which exhibit a“sustained-release” of the bupropion salt as used herein is defined tomean dosage forms administered once-daily that provide a release of thebupropion salt sufficient to provide a therapeutic dose soon afteradministration, and then a gradual release over an extended period oftime such that the sustained-release dosage form provides therapeuticbenefit over a 12 or 24-hour period.

“Extended- or sustained-release dosage forms” or dosage forms whichexhibit an “extended or sustained release” of the bupropion salt as usedherein is defined to include dosage forms administered once- ortwice-daily that release the bupropion salt slowly, so that plasmaconcentrations of the bupropion salt are maintained at a therapeuticlevel for an extended period of time such that the extended orsustained-release dosage form provides therapeutic benefit over a 12 or24-hour period.

“Prolonged-release dosage forms” or dosage forms which exhibit a“prolonged release” of the bupropion salt as used herein is defined tomean dosage forms administered once daily which provide for absorptionof the bupropion salt over a longer period of time than from aconventional, immediate release or uncoated normal release matrix dosageform and which provide therapeutic benefit over at least a 12 hour andmore typically at least a 24-hour period.

“Delayed-release dosage forms” or dosage forms which exhibit a “delayedrelease” of the bupropion salt as used herein is defined to mean dosageforms administered once-daily that do not effectively release drugimmediately following administration but at a later time.Delayed-release dosage forms provide a time delay prior to thecommencement of drug-absorption. This time delay is referred to as “lagtime” and should not be confused with “onset time” which representslatency, that is, the time required for the drug to reach minimumeffective concentration.

“Enhanced absorption dosage forms” or dosage forms which exhibit an“enhanced absorption” of the bupropion salt as used herein is defined tomean dosage forms that when exposed to like conditions, will show higherrelease and/or more absorption of the bupropion base as compared toother dosage forms with the same or higher amount of bupropion base. Thesame therapeutic effect can be achieved with less bupropion base in theenhanced absorption dosage form as compared to other dosage forms.

The term “controlled release matrix” as used herein is defined to mean adosage form in which the bupropion salt and combinations thereof isdispersed within a matrix, which matrix can be either insoluble,soluble, or a combination thereof. Controlled release matrix dosageforms of the insoluble type are also referred to as “insoluble polymermatrices”, “swellable matrices”, or “lipid matrices” depending on thecomponents that make up the matrix. Controlled release matrix dosageforms of the soluble type are also referred to as “hydrophilic colloidmatrices”, “erodible matrices”, or “reservoir systems”. Controlledrelease matrix dosage forms of the invention refer to dosage formscomprising an insoluble matrix, a soluble matrix or a combination ofinsoluble and soluble matrices in which the rate of release is slowerthan that of an uncoated non-matrix conventional or immediate releasedosage forms or uncoated “normal release matrix” dosage forms.Controlled release matrix dosage forms can be coated with a“control-releasing coat” to further slow the release of the bupropionsalt from the controlled release matrix dosage form. Such coatedcontrolled release matrix dosage forms can exhibit “modified-release”,controlled-release”, “sustained-release”, “extended-release”,“prolonged-release”, “delayed-release” or combinations thereof of thebupropion salt.

The term “normal release matrix” as used herein is defined to meandosage forms in which the bupropion salt and combinations thereof isdispersed within a matrix, which matrix can be either insoluble,soluble, or combinations thereof but constructed such that the releaseof the bupropion salt mimics the release rate of an uncoated non-matrixconventional or immediate release dosage form comprising the bupropionsalt. The release rate from normal release matrix dosage forms can beslowed down or modified in conjunction with a “control releasing coat”.

A “control releasing coat” or “controlled release coat” as used hereinis defined to mean a functional coat which can for example comprise atleast one pH independent polymer, pH dependent (such as for exampleenteric or reverse enteric types) polymer, soluble polymer, insolublepolymer, lipids, lipidic materials or combinations thereof which whenapplied onto a dosage form can slow (for example when applied to anormal release matrix dosage form), further slow (for example whenapplied to a controlled release matrix dosage form) or modify the rateof release of the bupropion salt when applied to an uncoated dosageform. For example, the control releasing coat can be designed such thatwhen the control releasing coat is applied to a dosage form, the dosageform in conjunction with the control releasing coat can exhibit therelease of the bupropion salt, such as for example, as a“modified-release”, “controlled-release”, “sustained-release”,“extended-release”, “delayed-release”, “prolonged-release” orcombinations thereof. The “control releasing coat” can optionallycomprise additional materials that can alter the functionality of thecontrol releasing coat.

The term “moisture barrier” as used herein is one, which impedes orretards the absorption of moisture. It is known that bupropion salts arehygroscopic and, as such, are susceptible to decomposition over timeunder high humidity conditions. The proportion of the components of themoisture barrier and the amount of the moisture barrier optionallyapplied onto the control-releasing coat or onto the core is typicallysuch that the moisture barrier does not fall within the USP definitionand requirement for an enteric coat. Suitably, the moisture barrier iscomprised of an enteric and/or acrylic polymer, suitably an acrylicpolymer, optionally a plasticizer, and a permeation enhancer. Thepermeation enhancer is a hydrophilic substance, which allows water toenter without physical disruption of the coating. The moisture barriermay additionally contain other conventional inert excipients, which mayimprove processing of the extended-release formulation described herein.

The term “medicament” as used hcrein refers to all possible oral andnon-oral dosage forms, including but not limited to, all modifiedrelease dosage forms, osmosis controlled release systems, erosioncontrolled release systems, dissolution controlled release systems,diffusion controlled release systems, matrix tablets, enteric coatedtablets, single and double coated tablets (including the extendedrelease and enhanced absorption tablets as described herein), capsules,minitablets, caplets, coated beads, granules, spheroids, pellets,microparticles, suspensions, topicals such as transdermal andtransmucoasal compositions and delivery systems (containing or notcontaining matrices), injectables, and inhalable compositions.

The term “chanced stability”, “greater stability”, “increased stability”or “more stable” as used herein when referring to a bupropion salt(bupropion HBr) means that the bupropion salt (bupropion hydrobromide),and compositions, formulations or medicaments comprising the bupropionsalt, when exposed to like conditions, i.e, when stored for at least 3months under accelerated storage conditions (40 degrees C., 75% relativehumidity) and/or when stored for at least 3, 4, 5 and/or 6 months or ayear or more under accelerated storage conditions (40 degrees C., 75%relative humidity) show less degradation as determined by the formationof less of at least one degradation product than an otherwise similarcomposition containing bupropion HCl. Additionally enhanced stability orgreater stability or increased stability of a bupropion salt (relativeto bupropion HCl) includes bupropion HBr compositions which exhibit moreconsistent dissolution profiles and therefore potency, compared to anotherwise similar bupropion hydrochloride formulation after being storedfor at least 3, 4, 5 and/or 6 months under the same accelerated storageconditions of 40 degrees C. and 75% relative humidity.

By “less degradation” it is meant any measurable decrease in the amountof at least one impurity characteristic of bupropion degradation or anymeasurable difference in the retention of potency relative to anotherwise similar bupropion HCl composition after being stored for atleast 3, 4, 5 and/or 6 months or longer, e.g, one or two years under theafore-identified accelerated storage conditions. The “degradationproducts” include those listed on page 281 of the 26th edition of theUSP and any other degradation products that may appear as peaks on achromatogram during the assay that are characteristic of bupropiondegradation.

As used herein “total impurities” mean all degradation productsresulting from the degradation of bupropion hydrobromide. The“degradation products” include those listed on page 281 of the 26thedition of the USP and any other degradation products that may appear aspeaks on a chromatogram during the assay.

The term “plasticizer” as used herein includes any compounds capable ofplasticizing or softening a polymer or a binder used in the presentinvention. The use of plasticizers is optional, and can be included inthe dosage form to modify the properties and characteristics of thepolymers used in the coat(s) or core of the dosage form for convenientprocessing during manufacture of the coat(s) and/or the core of thedosage form. Once the coat(s) and/or core has been manufactured, certainplasticizers can function to increase the hydrophilicity of the coat(s)and/or the core of the dosage form in the environment of use. Duringmanufacture of the coat(s) and/or core, the plasticizer can lower themelting temperature or glass transition temperature (softening pointtemperature) of the polymer or binder. Plasticizers can broaden theaverage molecular weight of a polymer in which they are included therebylowering its glass transition temperature or softening point.Plasticizers also can reduce the viscosity of a polymer. Plasticizerscan impart some particularly advantageous physical properties to thedosage forms of the invention.

The term “moiety” as used herein is defined to mean the molecule or ion,excluding those appended portions of the molecule that cause the drug tobe an ester, salt (including a salt with hydrogen or coordinationbonds), of the molecule, responsible for the physiological orpharmacological action of the drug substance.

The term “microparticle”, as used herein refers to a drug formulation indiscrete particulate form, and is interchangeable with the terms“microspheres”, “spherical particles”, “microcapsules”, “particles”,“multiparticulates”, “granules”, “spheroids”, beads” and “pellets”.

The term “core” as used here in is defined to mean any structure that issurrounded by a wall, membrane, or coating. The wall, membrane, orcoating can be a functional or non-functional coating.

The term “tablet” as used herein refers to a single dosage form, i.e.the single entity containing the active pharmaceutical agent that isadministered to the subject. The term “tablet” also includes a tabletthat may be the combination of one or more “minitablets”.

The term “osmosis” as used herein refers to the flow of a solventthrough a selectively-permeable membrane from a region of high solventpotential to a region of low solvent potential. Theselectively-permeable membrane must be permeable to the solvent, but notto the solute, resulting in a pressure gradient across the membrane.

The term “osmotic dosage form”, “osmotic delivery device”, “modifiedrelease osmotic dosage form” or “controlled release osmotic dosage form”as used herein is defined to mean dosage forms which forcibly dispensethe bupropion salt all or in part by pressure created by osmosis or by acombination of osmosis and diffusion of fluid into a dosage form whichforces the bupropion salt to be dispensed from the osmotic dosage form.The term “osmotic dosage form”, “osmotic delivery device”, “modifiedrelease osmotic dosage form”, or “controlled release osmotic dosageform” also encompasses such forms that can be coated with a “controlreleasing coat”.

The terms “osmagent”, “osmotic agent”, “osmotically effective solute”,“osmotic enhancer” “osmotically effective compounds”, “osmotic solutes”,or “osmotic fluid imbibing agents” are all used interchangeably hereinand define any material that increases the osmotic pressure of the core,thus, increasing the hydrostatic pressure inside the osmotic dosageform. The osmagent can be either soluble or swellable and totally orpartially solubilized. The osmagent can be the bupropion salt.

The term “pharmaceutically acceptable” means compatible with thetreatment of subjects, in particular, humans.

The term “subject” or “patient” as used herein means all members of theanimal kingdom, in particular, humans.

The term “effective amount” as used herein means a “pharmaceuticallyeffective amount”. A “pharmaceutically effective amount” is the amountor quantity of the bupropion salt or polymorph or anantiomer thereofwhich is sufficient to elicit an appreciable biological response whenadministered to a patient. It will be appreciated that the precisetherapeutic dose will depend on the age and condition of the patient andthe nature of the condition to be treated and will be at the ultimatediscretion of the attendant physician.

As used herein, and as well understood in the art, “treatment” is anapproach for obtaining beneficial or desired results, including clinicalresults. Beneficial or desired clinical results can include, but are notlimited to, alleviation or amelioration of one or more symptoms orconditions, diminishment of extent of disease, stabilized (i.e. notworsening) state of disease, preventing spread of disease, delay orslowing of disease progression, amelioration or palliation of thedisease state, and remission (whether partial or total), whetherdetectable or undetectable. “Treatment” can also mean prolongingsurvival as compared to expected survival if not receiving treatment.

“Palliating” a disease or disorder means that the extent and/orundesirable clinical manifestations of a disorder or a disease state arelessened and/or time course of the progression is slowed or lengthened,as compared to not treating the disorder.

The term “a” or “an” as used herein means “one” or “one or more”. Theterm “about” or “approximately” as used herein means within anacceptable error range for the particular value as determined by one ofordinary skill in the art, which will depend in part on how the value ismeasured or determined, i.e., the limitations of the measurement system.For example, “about” can mean within 1 or more than 1 standarddeviations, per practice in the art. Where particular values aredescribed in the application and claims, unless otherwise stated, theterm “about” means within an acceptable error range for the particularvalue.

Unless otherwise indicated, all numbers expressing quantities ofingredients, properties such as molecular weight, reaction conditions,and so forth used in the specification and claims are to be understoodas being modified in all instances by the term “about” Accordingly,unless indicated to the contrary, the numerical parameters set forth inthe following specification and attached claims are approximations thatmay vary depending upon the desired properties sought to be obtained bythe present invention. At the very least, and not as an attempt to limitthe application of the doctrine of equivalents to the scope of theclaims, each numerical parameter should at least be construed in lightof the number of reported significant digits and by applying ordinaryrounding techniques.

Other terms are defined as they appear in the following description andshould be construed in the context with which they appear.

DETAILED DESCRIPTION

There is a need for dosage forms comprising a pharmaceuticallyacceptable salt of bupropion that are more stable than otherwise similarcompositions containing bupropion hydrochloride. Accordingly, thepresent invention relates to dosage forms comprising an effective amountof bupropion hydrobromide that are more stable than bupropionhydrochloride. Also, the invention encompasses polmorphs thereof andspecific purified enantiomeric forms thereof. The present invention alsorelates to the use of such dosage forms for the treatment of one or moreconditions in a subject suitable for treatment by bupropion orpharmaceutically acceptable salts thereof such as depression, obesity,smoking cessation, and other conditions treatable with bupropion such asare disclosed herein.

Formulations

The present invention encompasses any medicament containing apharmaceutically effective amount of a stable bupropion salt accordingto the invention, i.e., bupropion hydrobromide. This includes both oraland non-orally administrable medicaments such as topicals, injectables,aerosols and other inhalable medicaments. Particularly such medicamentcompositions include orally administrable modified release dosage formcontaining the bupropion salt. The dosages can be conveniently presentedin unit dosage form and prepared by any of the methods well-known in theart of pharmacy.

“Dosage form” as used herein, means a pharmaceutical preparation thatcomprises an effective amount of a bupropion salt that is more stablethan bupropion hydrochloride. In at least one embodiment the bupropionsalt is bupropion hydrobromide.

A “solid dosage form” as used herein, means a dosage form that isneither liquid nor gaseous. Dosage forms include solid dosage forms,such as tablets, powders, microparticles, capsules, suppositories,sachets, troches, patches and losenges as well as liquid suspensions andelixirs. Capsule dosages contain the solid composition within a capsulethat can be made of gelatin or other conventional encapsulatingmaterial.

The modified release dosage forms contemplated in the present inventioncan be multiparticulate or monolithic. For example, those skilled in thepharmaceutical art and the design of medicaments are aware of modifiedrelease matricies conventionally used in oral pharmaceuticalcompositions adopted for modified release and means for theirpreparation. Examples of modified release formulations are disclosed inU.S. Pat. Nos. 5,591,452 and 5,965,161.

A modified release formulation containing the bupropion salt accordingto the present invention can be coated with one or more functional ornon-functional coatings. Examples of functional coatings includecontrolled release polymeric coatings (i.e. control releasing coats),moisture barrier coatings, enteric polymeric coatings, and the like.Non-functional coatings are coatings that do not affect drug release,but which affect other properties; such as the enhancement of thechemical, biological or physical stability characteristics, or theenhancement of the physical appearance of the formulation.

In at least one embodiment of the present invention the controlledrelease polymeric coating (or control-releasing coat) comprises anacrylic polymer. Suitable acrylic polymers include but are not limitedto acrylic acid and methacrylic acid copolymers, methyl methacrylatecopolymers, ethoxyethyl methacrylates, cynaoethyl methacrylate,aminoalkyl methacrylate copolymer, poly(acrylic acid), poly(methacrylicacid), methacrylic acid alkylamine copolymer, poly(methyl methacrylate),poly(methacrylic acid) (anhydride), polyacrylamide, poly(methacrylicacid anhydride), and glycidyl methacrylate copolymers.

In at least one embodiment polymerizable quaternary ammonium compoundsare employed in the control releasing coat, of which non-limitingexamples include quaternized aminoalkyl esters and aminoalkyl amides ofacrylic acid and methacrylic acid, for example3-methacryl-oxyethyl-trimethyl-ammonium methosulfate,-acryloxy-propyl-trimethyl-ammonium chloride, andtrimethylaminomethyl-methacrylamide methosulfate. The quaternaryammonium atom can also be part of a heterocycle, as inmethacryloxyethylmethyl-morpholiniom chloride or the correspondingpiperidinium salt, or it can be joined to an acrylic acid group or amethacrylic acid group by way of a group containing hetero atoms, suchas a polyglycol ether group. Further suitable polymerizable quaternaryammonium compounds include quaternized vinyl-substituted nitrogenheterocycles such as methyl-vinyl pyridinium salts, vinyl esters ofquaternized amino carboxylic acids, styryltrialkyl ammonium salts, andthe like. Other polymerizable quaternary ammonium compounds useful inthe present invention include acryl- andmethacryl-oxyethyltrimethyl-ammonium chloride and methosulfate,benzyldimethylammoniumethyl-methacrylate chloride,diethylmethylammoniumethyl-acrylate and -methacrylate methosulfate,N-trimethylammoniumpropylmethacrylamide chloride, andN-trimethylammonium-2,2-dimethylpropyl-1-methacrylate chloride.

In at least one embodiment the acrylic polymer is comprised of one ormore ammonio methacrylate copolymers. Ammonio methacrylate copolymers(such as those sold under the Trade Mark EUDRAGIT® RS and RL) aredescribed in National Formulary (NF) XVII as fully polymerizedcopolymers of acrylic and methacrylic acid esters with a low content ofquaternary ammonium groups. In order to obtain a desirable dissolutionprofile for a given therapeutically active agent, such as bupropionhydrobromide, two or more ammonio methacrylate copolymers havingdiffering physical properties can be incorporated. For example, it isknown that by changing the molar ratio of the quaternary ammonium groupsto the neutral (meth)acrylic esters, the permeability properties of theresultant coating can be modified.

In other embodiments of the present invention, the control releasingcoat further includes a polymer whose permeability is pH dependent, suchas anionic polymers synthesized from methacrylic acid and methacrylicacid methyl ester. Such polymers are commercially available, e.g., fromRohm Pharma GmbH under the tradename EUDRAGIT® L and EUDRAGIT® S. Theratio of free carboxyl groups to the esters is known to be 1:1 inEUDRAGIT® L and 1:2 in EUDRAGIT® S. EUDRAGIT® L is insoluble in acidsand pure water, but becomes increasingly permeable above pH 5.0.EUDRAGIT® S is similar, except that it becomes increasingly permeableabove pH 7. The hydrophobic acrylic polymer coatings can also include apolymer which is cationic in character based on dimethylaminoethylmethacrylate and neutral methacrylic acid esters (such as EUDRAGIT® E,commercially available from Rohm Pharma). The hydrophobic acrylicpolymer coatings of the present invention can further include a neutralcopolymer based on poly (meth)acrylates, such as EUDRAGIT® NE(NE=neutral ester), commercially available from Rohm Pharma. EUDRAGIT®NE 30D lacquer films are insoluble in water and digestive fluids, butpermeable and swellable.

In at least one other embodiment of the invention, the control releasingcoat comprises a dispersion of poly (ethylacrylate, methyl methacrylate)2:1 (KOLLICOAT® EMM 30 D, BASF).

In at least one other embodiment of the invention, the control releasingcoat comprises a polyvinyl acetate stabilized with polyvinylpyrrolidoneand sodium lauryl sulfate such as KOLLICOAT® SR30D (BASF). Thedissolution profile can by altered by changing the relative amounts ofdifferent acrylic resin lacquers included in the coating. Also, bychanging the molar ratio of polymerizable permeability-enhancing agent(e.g., the quaternary ammonium compounds) to the neutral (meth)acrylicesters, the permeability properties (and thus the dissolution profile)of the resultant coating can be modified.

In at least one embodiment of the invention the control releasing coatcomprises ethylcellulose, which can be used as a dry polymer (such asETHOCEL®, Dow Corning) solubilised in organic solvent prior to use, oras an aqueous dispersion. One suitable commercially-available aqueousdispersion of ethylcellulose is AQUACOAT® (FMC Corp., Philadelphia, Pa.,U.S.A.). AQUACOAT® can be prepared by dissolving the ethylcellulose in awater-immiscible organic solvent and then emulsifying the same in waterin the presence of a surfactant and a stabilizer. After homogenizationto generate submicron droplets, the organic solvent is evaporated undervacuum to form a pseudolatex. The plasticizer is not incorporated in thepseudolatex during the manufacturing phase. Thus, prior to using thesame as a coating, the AQUACOAT® can be intimately mixed with a suitableplasticizer prior to use. Another suitable aqueous dispersion ofethylcellulose is commercially available as SURELEASE® (Colorcon, Inc.,West Point, Pa., U.S.A.). This product can be prepared by incorporatingplasticizer into the dispersion during the manufacturing process. A hotmelt of a polymer, plasticizer (e.g. dibutyl sebacate), and stabilizer(e.g. oleic acid) is prepared as a homogeneous mixture, which is thendiluted with an alkaline solution to obtain an aqueous dispersion whichcan be applied directly onto substrates.

Other examples of polymers that can be used in the control-releasingcoat include cellulose acetate phthalate, cellulose acetate trimaletate,hydroxy propyl methylcellulose phthalate, polyvinyl acetate phthalate,polyvinyl alcohol phthalate, shellac; hydrogels and gel-formingmaterials, such as carboxyvinyl polymers, sodium alginate, sodiumcarmellose, calcium carmellose, sodium carboxymethyl starch, poly vinylalcohol, hydroxyethyl cellulose, methyl cellulose, ethyl cellulose,gelatin, starch, and cellulose based cross-linked polymers in which thedegree of crosslinking is low so as to facilitate adsorption of waterand expansion of the polymer matrix, hydroxypropyl cellulose,hydroxypropyl methylcellulose, polyvinylpyrrolidone, crosslinked starch,microcrystalline cellulose, chitin, pullulan, collagen, casein, agar,gum arabic, sodium carboxymethyl cellulose, (swellable hydrophilicpolymers) poly(hydroxyalkyl methacrylate) (molecular weight 5 k to 5000k), polyvinylpyrrolidone (molecular weight 10 k to 360 k), anionic andcationic hydrogels, zein, polyamides, polyvinyl alcohol having a lowacetate residual, a swellable mixture of agar and carboxymethylcellulose, copolymers of maleic anhydride and styrene, ethylene,propylene or isobutylene, pectin (molecular weight 30 k to 300 k),polysaccharides such as agar, acacia, karaya, tragacanth, algins andguar, polyacrylamides, POLYOX® polyethylene oxides (molecular weight 100k to 5000 k), AQUAKEEP® acrylate polymers, diesters of polyglucan,crosslinked polyvinyl alcohol and poly N-vinyl-2-pyrrolidone,hydrophilic polymers such as polysaccharides, methyl cellulose, sodiumor calcium carboxymethyl cellulose, hydroxypropyl methyl cellulose,hydroxypropyl cellulose, hydroxyethyl cellulose, nitro cellulose,carboxymethyl cellulose, cellulose ethers, methyl ethyl cellulose,ethylhydroxy ethylcellulose, cellulose acetate, cellulose butyrate,cellulose propionate, gelatin, starch, maltodextrin, pullulan, polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl acetate, glycerol fatty acidesters, polyacrylamide, polyacrylic acid, natural gums, lecithins,pectin, alginates, ammonia alginate, sodium, calcium, potassiumalginates, propylene glycol alginate, agar, and gums such as arabic,karaya, locust bean, tragacanth, carrageens, guar, xanthan, scleroglucanand mixtures and blends thereof.

In at least one embodiment of the invention the dosage forms are coatedwith polymers in order to facilitate mucoadhesion within thegastrointestinal tract. Non-limiting examples of polymers that can beused for mucoadhesion include carboxymethylcellulose, polyacrylic acid,CARBOPOL™, POLYCARBOPHIL™, gelatin and other natural or syntheticpolymers.

In at least one embodiment of the invention, the dosage form is anextended release tablet comprising: (i) a core that includes bupropionhydrobromide (e.g. from 40% to 99% by weight of tablet dry weight), abinder such as polyvinyl alcohol (e.g. from 0.5% to 25% by weight oftablet dry weight), and a lubricant such as glyceryl behenate (e.g. from0.1% to 5% by weight of tablet dry weight); and (ii) a control releasingcoat that includes a water-insoluble water-permeable film-formingpolymer such as ethylcellulose (e.g. from 1% to 12% by weight of tabletdry weight), a water-soluble polymer such as polyvinylpyrrolidone(POVIDONE® USP), (e.g. from 1.5% to 10% by weight of tablet dry weight),optionally a plasticizer such as dibutyl sebacate, polyethylene glycol4000 or a mixture thereof (e.g. from 0.5% to 4% by weight of tablet dryweight), and optionally a wax such as carnauba wax (e.g. from 0.01% to0.05% by weight of tablet dry weight).

In at least one embodiment of the invention, the dosage form is a 174 mgXL tablet comprising: (i) a core that includes bupropion hydrobromide(e.g. 81% by weight of tablet dry weight), a binder such as polyvinylalcohol (e.g. 3% by weight of tablet dry weight), and a lubricant suchas glyceryl behenate (e.g. 3% by weight of tablet dry weight); and (ii)a control releasing coat that includes a water-insoluble water-permeablefilm-forming polymer such as ethylcellulose (e.g. 8% by weight of tabletdry weight), a water-soluble polymer such as polyvinylpyrrolidone(POVIDONE® USP), (e.g. 5% by weight of tablet dry weight), optionally aplasticizer such as dibutyl sebacate, polyethylene glycol 4000 or amixture thereof (e.g. 3% by weight of tablet dry weight), and optionallya wax such as carnauba wax (e.g. 0.03% by weight of tablet dry weight).

In at least one embodiment of the invention, the dosage form is a 348 mgXL tablet comprising: (i) a core that includes bupropion hydrobromide(e.g. 87% by weight of tablet dry weight), a binder such as polyvinylalcohol (e.g. 3% by weight of tablet dry weight), and a lubricant suchas glyceryl behenate (e.g. 3% by weight of tablet dry weight); and (ii)a control releasing coat that includes a water-insoluble water-permeablefilm-forming polymer such as ethylcellulose (e.g. 4% by weight of tabletdry weight), a water-soluble polymer such as polyvinylpyrrolidone(POVIDONE® USP), (e.g. 3% by weight of tablet dry weight), optionally aplasticizer such as dibutyl sebacate, polyethylene glycol 4000 or amixture thereof (e.g. 2% by weight of tablet dry weight), and optionallya wax such as carnauba wax (e.g. 0.01% by weight of tablet dry weight).

In addition to the modified release dosage forms described herein, othermodified release technologies known to those skilled in the art can beused in order to achieve the modified release formulations of thepresent invention, i.e., formulations which provide a mean T_(max) ofthe drug and/or other pharmacokinetic parameters described herein whenadministered e.g., orally or by other mode of administration to humanpatients. Such formulations can be manufactured as a modified releaseoral formulation in a suitable tablet or multiparticulate formulationknown to those skilled in the art. In either case, the modified releasedosage form can optionally include a controlled release carrier which isincorporated into a matrix along with the drug, or which is applied as acontrolled release coating.

Tablets

In another specific aspect of the present invention, there is provided amodified-release tablet having a core comprising a pharmaceuticallyacceptable salt of bupropion and conventional excipients, wherein thebupropion salt is more stable than bupropion hydrochloride (bupropionhydrobromide). The core can be surrounded by a control-releasing coatwhich controls the release of the bupropion salt. In other embodiments,a moisture barrier can optionally be added to surround thecontrol-releasing coat. This moisture barrier is optional given theenhanced stability of bupropion HBr relative to bupropion HCl and byselection of an appropriate control-releasing coats and amount thereof.If present, this moisture barrier may affect in vitro drug release aswell as precluding moisture from coming into contact with the bupropionsalt. Optionally, this tablet may further comprise one or moreadditional functional or non-functional coatings surrounding the core,moisture barrier and/or control-releasing coat.

Extended Release (XL) Tablets

In another specific aspect of the present invention, there is providedan extended-release (XL) tablet having a core comprising apharmaceutically acceptable salt of bupropion and conventionalexcipients, wherein the bupropion salt is more stable than bupropionhydrochloride. In at least one embodiment the bupropion salt isbupropion hydrobromide. The core can be surrounded by acontrol-releasing coat, which controls the release of the bupropionsalt. The tablet optionally may comprise one or more additionalfunctional or non-functional coats surrounding the core orcontrol-releasing coat. The extended-release tablet of the invention hasunexpected enhanced stability.

The XL Core

The core of the extended-release tablet comprises an effective amount ofa bupropion salt, a binder, and a lubricant and can contain otherconventional inert excipients. In at least one embodiment the bupropionsalt is bupropion hydrobromide. The amount of the bupropion salt presentin the XL core can vary in an amount from 40% to 99% by weight of thetablet dry weight. For example, in certain embodiments bupropionhydrobromide is present in an amount from 70% to 95% by weight of thetablet dry weight. For example, in certain embodiments, the core of thedosage form of the present invention comprises bupropion hydrobromide ina proportion of 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%,95% or 99% of the core dry weight. The tablet comprises an effectiveamount of bupropion salt that typically will vary from 50 mg to 450 mg.For example, in certain embodiments, the tablet comprises 174 mg ofbupropion hydrobromide, and in other embodiments the tablet comprises348 mg of bupropion hydrobromide. In at least one embodiment of a 174 mgdose tablet, the bupropion hydrobromide is present at from 75% to 85% byweight of the tablet dry weight. In at least one embodiment of a 348 mgdose tablet, the amount of bupropion hydrobromide can be present at from80% to 90% by weight of the tablet dry weight. In certain embodiments ofboth the 174 mg and 348 mg dose bupropion hydrobromide extended-releasetablets of the invention, the amount of bupropion hydrobromide ispresent from 90% to 99% by weight of the dry core for each dose.

A binder (also sometimes called adhesive) can be added to a drug-fillermixture to increase the mechanical strength of the granules and tabletsduring formation. Binders can be added to the formulation in differentways: (1) as a dry powder, which is mixed with other ingredients beforewet agglomeration, (2) as a solution, which is used as agglomerationliquid during wet agglomeration, and is referred to as a solutionbinder, and (3) as a dry powder, which is mixed with the otheringredients before compaction. In this form the binder is referred to asa dry binder. Solution binders are a common way of incorporating abinder into granules. In certain embodiments, the binder used in the XLtablets is in the form of a solution binder. Non-limiting examples ofbinders useful for the core include hydrogenated vegetable oil, castoroil, paraffin, higher aliphatic alcohols, higher alphatic acids, longchain fatty acids, fatty acid esters, wax-like materials such as fattyalcohols, fatty acid esters, fatty acid glycerides, hydrogenated fats,hydrocarbons, normal waxes, stearic acid, stearyl alcohol, hydrophobicand hydrophilic polymers having hydrocarbon backbones, and mixturesthereof. Specific examples of water-soluble polymer binders includemodified starch, gelatin, polyvinylpyrrolidone, cellulose derivatives(such as for example hydroxypropyl methylcellulose (HPMC) andhydroxypropyl cellulose (HPC)), polyvinyl alcohol and mixtures thereof.The amount of binder present can vary from 0.5% to 25% by weight of thetablet dry weight. For example, in certain embodiments the binder ispresent in an amount of from 0.5% to 15% by weight of the tablet dryweight; in other embodiments from 1% to 6% by weight of the tablet dryweight; and in still other embodiments at 3% by weight of the tablet dryweight. For example, in certain embodiments of both the 174 mg and 348mg dose tablets, the binder is present in an amount of from 1% to 6% byweight of each dry core weight, and in other embodiments at 3% by weightof each dry core weight. In at least one embodiment of the invention thebinder is polyvinyl alcohol.

Lubricants can be added to pharmaceutical formulations to decrease anyfriction that occurs between the solid and the die wall during tabletmanufacturing. High friction during tabletting can cause a series ofproblems, including inadequate tablet quality (capping or evenfragmentation of tablets during ejection, and vertical scratches ontablet edges) and may even stop production. Accordingly, lubricants areadded to certain tablet formulations of the present invention includingcertain embodiments of the XL tablet formulation described herein.Non-limiting examples of lubricants useful for the core include glycerylbehenate, stearic acid, hydrogenated vegetable oils (such ashydrogenated cottonseed oil (STEROTEX®), hydrogenated soybean oil(STEROTEX® HM) and hydrogenated soybean oil & castor wax (STEROTEX® K),stearyl alcohol, leucine, polyethylene glycol (MW 1450, suitably 4000,and higher), magnesium stearate, glyceryl monostearate, stearic acid,polyethylene glycol, ethylene oxide polymers (for example, availableunder the registered trademark CARBOWAX® from Union Carbide, Inc.,Danbury, Conn.), sodium lauryl sulfate, magnesium lauryl sulfate, sodiumolcate, sodium stearyl fumarate, DL-leucine, colloidal silica, mixturesthereof and others as known in the art. In at least one embodiment ofthe present invention, the lubricant is glyceryl behenate (for example,COMPRITOL® 888). The amount of lubricant present can vary from 0.1% to6% by weight of the tablet dry weight. For example, in certainembodiments the amount of lubricant present is from 2% to 3% by weightof the tablet dry weight; and in other embodiments the amount oflubricant present is at 3% by weight of the tablet dry weight. Incertain embodiments of the 174 mg and 348 mg dose XL tablets of theinvention, the lubricant is present in an amount of 3% by weight of thetablet dry weight, or from 1% to 6% by weight of the dry core weight.For example, in certain embodiments the lubricant is present in anamount of 3% by weight of the dry core weight for both the 174 mg and348 mg dose XL tablets.

At this stage, the XL core formulation of certain embodiments of thepresent invention, is an uncoated immediate release formulationresulting in 100% dissolution of the bupropion salt within 1 hour. In atleast one embodiment the XL core is a normal release matrix formulation.In certain embodiments the core comprises an effective pharmaceuticalamount of bupropion hydrobromide, a binder (e.g. polyvinyl alcohol), anda lubricant (e.g. glyceryl behenate). Additional inert excipientsconsistent with the objects of the invention can also be added to thecore formulation. The additional inert excipients can be added tofacilitate the preparation and/or improve patient acceptability of thefinal extended-release dosage form as described herein. The additionalinert excipients are well known to the skilled artisan and can be foundin the relevant literature, for example in the Handbook ofPharmaceutical Excipients. Non-limiting examples of such excipientsinclude spray dried lactose, sorbitol, mannitol, and any cellulosederivative.

In at least one embodiment of the invention, the granules to becompressed to form the core of the XL tablet of the invention describedherein, are manufactured by the wet granulation process. Wet granulationinvolves agitation of a powder (the active drug) by convention in thepresence of a liquid (the solution binder) followed by drying. Forforming the granules, which are to be eventually compressed into thetablet cores, the bupropion salt is first granulated, for example, witha solution binder, in a granulator, for example using a fluidized bedgranulator (e.g. a fluidized bed granulator manufactured by Glatt(Germany) or Aeromatic (Switzerland)). The binder (e.g. polyvinylalcohol) is first dissolved or dispersed in a suitable solvent (e.g.water). The solution binder is then top sprayed onto the drug in agranulator (e.g. a fluidized bed granulator). Alternatively, granulationcan also be performed in a conventional or high shear mixer. Ifnecessary, the additional inert excipients (e.g. a filler) can be mixedwith the bupropion salt prior to the granulation step.

The granules formed are subsequently dried and then sieved prior toblending the granules with the lubricant. In certain embodiments, thedried granules are sieved through a 1.4 mm mesh screen. The sievedgranules are then blended with the lubricant, and if necessary, anyother additional inert excipients, which can improve processing of theextended-release tablets of the invention. Blending of the granules withthe lubricant, and if necessary, any additional inert excipients, suchas for example a glidant, can be performed in a V-blender or any othersuitable blending apparatus. Glidants can improve the flowability of thepowder. This is especially important during tablet production at highproduction speeds and during direct compaction. However, because therequirement for adequate flow is high, a glidant is often also added toa granulation before tabletting. The blended granules are subsequentlypressed into tablets and are hereinafter referred to as tablet cores.Tablet cores can be obtained by the use of standard techniques andequipment well known to the skilled artisan. For example, the XL tabletcores can be obtained by a rotary press (also referred to as amulti-station press) fitted with suitable punches.

The granules can also be manufactured by using other processes known tothe skilled artisan. Examples of other granule manufacturing processesinclude dry granulation (e.g. slugging, roller compaction), directcompression, extrusion, spheronization, melt granulation, and rotarygranulation.

An example of the granulation process for the XL cores (60 kg batch) isas follows: A Fluid Bed Processor is used for granulation in order toagglomerate the particles of the materials to obtain a uniform particlesize for the final blend. The granulating solution is prepared bydissolving the binder (e.g. polyvinyl alcohol) in hot purified waterwhile mixing. The percent solids content can be adjusted to obtain aviscosity to control the build up (agglomeration size) of the material.A lower viscosity leads to smaller particles, and a higher viscosityleads to larger particles. In addition, the application rate (e.g. from150 gm/min to 250 gm/min; or 200 gm/min), position of Spray gun (e.g.center position) and nozzle size (e.g. from 0.5 mm to 2 mm; or 1 mm) andatomization pressure (e.g. from 20 psi to 40 psi; or 30 psi) contributefurther to control particle size. The active material is fluidized andheated (e.g. from 35° C. to 45° C.; or 40° C.) prior to start ofsolution application. During the spray cycle, the bed temperature (e.g.from 35° C. to 45° C.; or 40° C.) is kept at a constant temperature toavoid over-wetting. Once all the required binder solution is applied,the material is further dried to the targeted LOD value (i.e. loss ondrying) (e.g. below 1%) prior to unloading. The amount of binder (e.g.polyvinyl alcohol) is between 2% to 6%, and in some cases 3%; and thesolution concentration is between 3% to 7%, and in some cases 4.5%. Thetime of agglomeration process for the 60 kg batch is between 45 minutesto 220 minutes, and in some cases 150 minutes. Once the granulate isdry, material is passed through a 1.4 and 2.00 mm screen to remove anyoversized particles. The oversize particles are passed through the millto reduce oversize particles. Oversized particles generally not toexceed 5% of total yield. The screened and milled materials are placedinto a shell blender (e.g. V-Blender, Bin blender) and the lubricant(e.g. glyceryl behenate) is added. The lubricant is screened and addedto the granules and blended at the predetermined number of revolutionsor time (e.g. mix time of 5 min to 15 min, and in some cases 10 min).The percent lubricant is between 0.5% to 4%, and in some cases 2%. Thelevel of lubrication is established for sufficient coverage of eitherlarger or smaller particle size distribution. Additional characteristicsinclude bulk density (e.g. from 0.3 gm/ml to 0.8 gm/ml, and in somecases 0.5 gm/ml), and moisture content (e.g. not more than 1%). Particlesize and flow of final blend are factors in obtaining uniform fill ofcavities on a rotary press. The flow and top rotation speed of the pressare adjusted (dependant on the type/size of press) so as to notjeopardize the weight uniformity of individual tablets. The productblend is passed through a hopper into a feed frame to fill the diecavities passing under the feed frame. Weight adjustments are made tokeep the weight within the specified range, and adjustments made to thepressure settings to obtain the required hardness. Some componentsmonitored for the tablets are tablet thickness and friability (e.g. lessthan 0.5%). Suitable thickness (related to overall surface area) andlower friability help reduce core damage and loss of active duringcoating. Tablet samples are removed at predetermined intervals tomonitor specifications.

Coatings

The tablet cores can be coated for administration to a subject. In atleast one embodiment of the invention, the tablet cores are coated withan extended release control-releasing coating (“XL Control-ReleasingCoat”). In at least one other embodiment, the tablet cores are coatedwith an aqueous control-releasing coating that comprises an aqueousdispersion of a neutral ester copolymer without any functional groups(“AQ Control-Releasing Coat”).

In certain embodiments the tablet dosage form comprises an optionalmoisture barrier in addition to the control-releasing coat. Thecontrol-releasing coat and the moisture barrier can be applied in twostages. The control-releasing coating can be applied directly onto thesurface of the tablet cores and functions to control the release of thebupropion salt. The moisture barrier can be applied directly onto thesurface of the control-releasing coat to impede or retard the absorptionof moisture.

Prophetic examples of control-releasing coat formulations are providedbelow. It should be understood that the constituents and/or proportionsof the constituents in these coatings as well as the amounts thereof maybe varied in order to achieve formulations possessing different releasecharacteristics. In all instances wherein prophetic examples areprovided these compositions are intended to be exemplary and it shouldbe understood that the specific procedures, constituents, amountsthereof and the like may be varied in order to obtain a compositionpossessing desired properties.

In at least one embodiment the control-releasing coat is a delayedrelease coating formulation for a tablet core, the coating formulationto be applied to the core comprising:

Eudragit L12.5 50% by weight of coating suspension Triethyl citrate0.63% by weight of coating suspension Talc 1.25% by weight of coatingsuspension Isopropyl alcohol 48.12% by weight of coating suspensionSolids total = 8.1% Polymer content of suspension = 6.3%

Preparation of the delayed release coating formulation can be asfollows: Talc and triethyl citrate are homogenized in the solvent bymeans of a homogenizer for approximately 10 minutes. The suspension ispoured directly into the EUDRAGIT® L12.5 dispersion and stirred gentlyto avoid sedimentation. The coating is sprayed onto tablets untilapproximately 5 mg/cm2 of EUDRAGIT® L has been applied to the tabletcore.

In at least one embodiment the control-releasing coat is a sustainedrelease coating formulation for a tablet core, the coating formulationapplied to the core comprising:

Eudragit RL 12.5 10% by weight of coating suspension Eudragit RS 12.530% by weight of coating suspension Dibutyl sebacate 0.5% by weight ofcoating suspension Talc 3.5 g by weight of coating suspension Magnesiumstearate 1% by weight of coating suspension Acetone 27.5% by weight ofcoating suspension Isopropyl alcohol 27.5% by weight of coatingsuspension Solids total = 10% Polymer content of suspension = 5%

Preparation of the sustained release coating formulation can be asfollows: Dibutyl sebacate, talc and magnesium stearate are mixed andfinely dispersed together with the diluents acetone and isopropylalcohol. The suspension is then combined with the EUDRAGIT® polymerdispersions. The coating is sprayed onto the core until approximately 10mg/cm2 of polymer has been applied to the core.

In at least one embodiment the control-releasing coat is a polymer blendcoating possessing pH dependent polymer (EUDRAGIT® L 30D 55) incombination with a sustained release polymer (AQUACOAT®), the coatingformulation applied to the core comprising:

Aquacoat (ethylcellulose 30%) 21% by weight of coating suspensionEudragit L30 D 55 21% by weight of coating suspension Triethyl citrate3% by weight of coating suspension Water 55% by weight of coatingsuspension Solids total = 15.6% Polymer content of suspension = 12.6%

Application of the polymer blend coating can be as follows: Coatingapplied to a 10 mg/cm² application of polymer to the drug core.

In at least one embodiment the control-releasing coat is a drug coating(Citalopram) on top of a bupropion salt core, the coating formulationapplied to the core comprising:

Kollidon VA64 2.5% by weight of drug coating suspension(Vinylpyrrolidone-vinyl acetate copolymer) KLUCEL ™EF 2.5% by weight ofdrug coating suspension (Hydroxypropylcellulose) Citalopram 2% by weightof drug coating suspension Talc 3% by weight of drug coating suspension2-propanol 90% by weight of drug coating suspension Solids total = 10%Polymer content of suspension = 5%

Application of the drug coating formulation can be as follows: Drugcoating is sprayed onto tablets until the desired amount of Citalopramis applied. A top-coat can subsequently be applied as a cosmetic coatingand also to prevent tablet sticking, the top-coat formulation applied tothe drug coated core comprising:

Kollidon VA64 2.5% by weight of top-coat suspension(Vinylpyrrolidone-vinyl acetate copolymer) KLUCEL ™ EF 2.5% by weight oftop-coat suspension (Hydroxypropylcellulose) Talc 2.5% by weight oftop-coat suspension Isopropyl alcohol 92.5% by weight of top-coatsuspension Solids total = 7.5% Polymer content of suspension = 5%

Application of the top-coating formulation can be as follows: Coating isapplied to a 2% weight gain (expressed as % of drug coated tablet core)

The Extended Release (XL) Control-Releasing Coat

The XL control-releasing coat is a semi-permeable coat comprising awater-insoluble, water-permeable film-forming polymer, optionally awater-soluble polymer, and optionally a plasticizer.

Non-limiting examples of water-insoluble, water-permeable film-formingpolymers useful for the XL control-releasing coat include celluloseethers, cellulose esters, and polyvinyl alcohol. For example, thewater-insoluble, water-permeable film forming polymers can be the ethylcelluloses, and can be selected from the following: ethyl cellulosegrades PR100, PR45, PR20, PR10 and PR7 (ETHOCEL®, Dow), and anycombination thereof. In at least one embodiment of the invention, ethylcellulose grade PR 100 is the water-insoluble, water-permeablefilm-forming polymer. The amount of the water-insoluble water-permeablefilm-forming polymer can vary from 1% to 12% by weight of the tablet dryweight. For example, in certain embodiments the amount of thewater-insoluble water-permeable film-forming polymer is present in anamount from 5% to 10%, and in other embodiments from 6% to 8% by weightof the tablet dry weight. In certain embodiments of the 174 mg dosemodified-release tablets of the invention, the amount of water-insolublewater permeable film-forming polymer is from 3% to 8% by weight of thetablet dry weight, and in other embodiments from 6% to 7% by weight ofthe tablet dry weight. With respect to the control-releasing coatitself, the amount of water-insoluble water-permeable film-formingpolymer in certain embodiments of the 174 mg dose tablet is from 35% to60% by weight of the control-releasing coat dry weight, and in otherembodiments from 40% to 50% by weight of the control-releasing coat dryweight. In certain embodiments of the 348 mg dose modified-releasetablet of the invention, the amount of water-insoluble water-permeablefilm-forming polymer is from 2% to 5% by weight of the tablet dryweight, and in other embodiments from 3% to 4% by weight of the tabletdry weight. With respect to the control-releasing coat itself, thewater-insoluble water-permeable film-forming polymer in certainembodiments of the 348 mg dose tablet is present in an amount of 40% byweight of the control-releasing coat dry weight.

Non-limiting examples of water-soluble polymers useful for the XLcontrol-releasing coat include polyvinylpyrrolidone, hydroxypropylmethylcellulose, hydroxypropyl cellulose and mixtures thereof. In atleast one embodiment the water-soluble polymer is polyvinylpyrrolidone(POVIDONE® USP). The amount of water-soluble polymer can vary from 1.5%to 10% by weight of the tablet dry weight. For example, in certainembodiments the amount of water-soluble polymer is from 3% to 8%, and inother embodiments at 4% by weight of the tablet dry weight. With respectto the control-releasing coat itself, in certain embodiments the amountof water-soluble polymer present is from 25% to 55% by weight of thecontrol-releasing coat dry weight. For certain embodiments of the 174 mgdose of the extended release tablet of the invention, the amount ofwater-soluble polymer is from 3% to 5% by weight of the tablet dryweight, and from 25% to 50% by weight of the control-releasing coat dryweight. For certain embodiments of the 348 mg dose of the extendedrelease tablet of the invention, the amount of water-soluble polymerpresent is from 2% to 5% of the tablet dry weight and 40% to 50% byweight of the control-releasing coat dry weight.

In certain embodiments, the XL control-releasing coat further comprisesa plasticizer. The use of plasticizers is optional, and they can beadded to film coating formulations to modify the physical properties ofa polymer to make it more usable during manufacturing. Plasticizers canbe high boiling point organic solvents used to impart flexibility tootherwise hard or brittle polymeric materials. Plasticizers generallycause a reduction in the cohesive intermolecular forces along thepolymer chains resulting in various changes in polymer propertiesincluding a reduction in tensile strength, and increase in elongationand a reduction in the glass transition or softening temperature of thepolymer. The amount and choice of the plasticizer can affect thehardness of a tablet and can even affect its dissolution ordisintegration characteristics, as well as its physical and chemicalstability. Certain plasticizers can increase the elasticity and/orpliability of a coat, thereby decreasing the coat's brittleness. Oncethe dosage form is manufactured, certain plasticizers can function toincrease the hydrophilicity of the coat(s) and/or the core of the dosageform in the environment of use (in-vitro or in-vivo). Non-limitingexamples of plasticizers that can be used in the control-releasing coatdescribed herein include acetylated monoglycerides; acetyltributylcitrate, butyl phthalyl butyl glycolate; dibutyl tartrate; diethylphthalate; dimethyl phthalate; ethyl phthalyl ethyl glycolate; glycerin;propylene glycol; triacetin; tripropioin; diacetin; dibutyl phthalate;acetyl monoglyceride; acetyltriethyl citrate, polyethylene glycols;castor oil; rape seed oil, olive oil, sesame oil, triethyl citrate;polyhydric alcohols, glycerol, glycerin sorbitol, acetate esters,gylcerol triacetate, acetyl triethyl citrate, dibenzyl phthalate,dihexyl phthalate, butyl octyl phthalate, diisononyl phthalate, butyloctyl phthalate, dioctyl azelate, epoxidized tallate, triisoctyltrimellitate, diethylhexyl phthalate, di-n-octyl phthalate, di-i-octylphthalate, di-i-decyl phthalate, di-n-undecyl phthalate, di-n-tridecylphthalate, tri-2-ethylhexyl trimellitate, di-2-ethylhexyl adipate,di-2-ethylhexyl sebacate, di-2-ethylhexyl azelate, dibutyl sebacate,diethyloxalate, diethylmalate, diethylfumerate, dibutylsuccinate,diethylmalonate, dibutylphthalate, dibutylsebacate, glyceroltributyrate,polyols (e.g. polyethylene glycol) of various molecular weights, andmixtures thereof. It is contemplated and within the scope of theinvention, that a combination of plasticizers can be used in the presentformulation. In at least one embodiment of the invention, the plastizeris polyethylene glycol 4000, dibutyl sebacate or a mixture thereof. Theamount of plasticizer for the control-releasing coat can vary in anamount of from 0.5% to 4% by weight of the tablet dry weight. Forexample, in certain embodiments the plasticizer is present in an amountof from 2% to 3% by weight of the tablet dry weight. For certainembodiments of the 174 mg dose extended-release tablet of the invention,the amount of plasticizer present in the control-releasing coat is from1% to 4% by weight of the tablet dry weight. For certain embodiments ofthe 348 mg dose extended-release tablet of the invention, the amount ofplasticizer present is from 0.5% to 4% by weight of the tablet dryweight. In certain embodiments of both the 174 mg and 348 mg dosageforms, the plasticizer is present in an amount of from 6% to 30% byweight of the control-releasing coat dry weight. For example, in certainembodiments the plasticizer is present in an amount of 12% by weight ofthe control-releasing coat dry weight.

The ratio of water-insoluble water-permeable film formingpolymer:plasticizer:water-soluble polymer for the XL control releasingcoat of the invention described herein can vary from 3:1:4 to 5:1:2. Forexample, in certain embodiments the ratio of water-insolublewater-permeable film forming polymer:plasticizer:water-soluble polymerfor the XL control releasing coat is 4:1:3. For certain embodiments ofthe XL tablet the ratio of the water-insoluble water-impermeablefilm-forming polymer:plasticizer:water-soluble polymer in the XL controlreleasing coat is from 7:2:6 to 19:5:18. In at least one embodiment theratio of water-insoluble water-permeable film formingpolymer:plasticizer:water-soluble polymer for the XL control releasingcoat is 13:4:12.

Preparation and application of the XL control-releasing coat can be asfollows. The water-insoluble water-permeable film-forming polymer (e.g.ethylcellulose), and the plasticizer (e.g. polyethylene glycol 4000),are dissolved in an organic solvent (e.g. a mixture of ethyl alcohol).In the manufacture of embodiments that do not require a plasticizer, thewater-insoluble water-permeable film-forming polymer can be dissolved inthe organic solvent without the plasticizer. The water-soluble polymer(e.g. polyvinyl pyrrolidone) is next added until a homogenous mixture isachieved. The resulting control-releasing coat solution is then sprayedonto the tablet cores using a tablet coater, fluidized bed apparatus orany other suitable coating apparatus known in the art until the desiredweight gain is achieved. The tablet cores coated with thecontrol-releasing coat are subsequently dried. In the manufacture ofembodiments that have a moisture barrier, the control-releasing coat isdried before the moisture barrier is applied.

An example of the coating process for the XL control releasing coat isas follows: The XL control releasing coat solution is prepared bydissolving the water insoluble polymer (e.g. ethylcellulose) and watersoluble polymer (e.g. polyvinylpyrrolidone) and an ethyl alcohol mixturewhile mixing and is followed with the addition of the plasticizer(s)(e.g. polyethylene glycol 4000 and dibutyl sebacate). Once completelydissolved, the solution is homogenized to obtain a uniform mixture ofappropriate viscosity. This procedure assures a complex mix of a waterpermeable film to control the release of the active drug. Thecomposition of the solution can be formulated to contain various levelsof the water insoluble polymer and water soluble polymer and a mix ofthe plasticizer(s). The release function is further controlled by thefilm thickness applied and measured as weight gain of solids in thecoating required. Tablets are coated in a perforated coating pan withcontrol of pan speed (e.g. from 8 rpm to 14 rpm, and in some cases 12rpm), spray rate (e.g. from 150 gm/min to 250 gm/min, and in some cases200 gm/min), atomization pressure (e.g. from 15 psi to 25 psi, and insome cases 20 psi), supply volume (from 800 to 1000 cubic ft/min, and insome cases 900 cubic ft/min), and air temperature (e.g. from 50° C. to60° C., and in some cases 55° C.), monitored through a bed temperatureand/or outlet temperature of from 38° C. to 42° C., and in some cases40° C. On completion of the coating cycle, tablets are dried andunloaded into bulk containers. The printing process comprises thetransfer of a print image from a print plate covered with edible blackink and transferred via a print roll or print pad onto the surface ofthe tablets. The printed tablets are transferred through a dryingelement prior to discharging into bulk containers. Samples for finaltesting are taken throughout the printing process.

The skilled artisan will appreciate that controlling the permeabilitycan control the release of the bupropion salt and/or the amount ofcoating applied to the tablet cores. The permeability of the XLcontrol-releasing coat, can be altered by varying the ratio of thewater-insoluble, water-permeable film-formingpolymer:plasticizer:water-soluble polymer and/or the quantity of coatingapplied to the tablet core. A more extended release can be obtained witha higher amount of water-insoluble, water-permeable film formingpolymer. The addition of other excipients to the tablet core can alsoalter the permeability of the control-releasing coat. For example, if itis desired that the tablet core further comprise an expanding agent, theamount of plasticizer in the control-releasing coat could be increasedto make the coat more pliable, as the pressure exerted on a less pliablecoat by the expanding agent could rupture the coat. Further, theproportion of the water-insoluble water-permeable film forming polymerand water-soluble polymer can also be altered depending on whether afaster or slower dissolution and/or release profile is desired.

Depending on the dissolution or in-vivo release profile desired, theweight gained after coating the tablet core with the XLcontrol-releasing coat typically will vary from 3% to 30% of the weightof the dry tablet core. For a 174 mg dose extended release tabletaccording to the present invention, the weight gain can typically varyfrom 10% to 17% of the weight of the dry tablet core. For example incertain embodiments, the weight gain is 14% of the weight of the drytablet core. For the 348 mg dose extended release tablet of the presentinvention, the weight gain can vary from 7% to 10% of the weight of thedry tablet core. For example in certain embodiments, the weight gain is9% of the weight of the dry tablet core.

AQ Control-Releasing Coat

The AQ control-releasing coat is a stable monolithic controlled releasecoating comprising an aqueous dispersion of a neutral ester copolymerwithout any functional groups, a poly glycol having a melting pointgreater than 55° C., and one or more pharmaceutically acceptableexcipients; wherein said coating composition is coated onto the dosageform and cured at a temperature at least equal to or greater than themelting point of the poly glycol. The coating formulation is quiteversatile in that it can be used to coat a variety of drug cores and canbe easily manipulated to obtain the desired drug release profile.

In certain other embodiments, the AQ control-releasing coat comprises anaqueous dispersion of an ethylcellulose, a poly glycol having a meltingpoint greater than 55° C., and one or more pharmaceutically acceptableexcipients; wherein said coating composition is coated onto the dosageform and cured at a temperature at least equal to or greater than themelting point of the poly glycol. Non limiting examples of aqueousdispersions of an ethylcellulose include SURELEASE® (Colorcon, Inc.,West Point, Pa., U.S.A.), and AQUACOAT® (FMC Corp., Philadelphia, Pa.,U.S.A.).

Non-limiting examples of neutral ester copolymers without any functionalgroups that can be used in the AQ control-releasing coat includeEUDRAGIT® NE30D, EUDRAGIT® NE40D (Röhm America LLC), and mixturesthereof. In at least one embodiment the polymer is Eudragit NE30D, whichcan be present in an amount of from 1% to 35% by weight of thecontrol-releasing coat, depending on the controlled release profiledesired. Hydrophilic agents can also be included in the AQcontrol-releasing coat to promote wetting of the coat when in contactwith gastrointestinal fluids. Non-limiting examples of such hydrophilicagents include hydrophilic water soluble polymers such as hydroxypropylmethylcellulose (HPMC), hydroxypropyl cellulose (HPC) and combinationsthereof. In at least one embodiment, HPMC is the hydrophilic watersoluble polymer. If hydrophilic agents are to be included in the coatcomposition, the agents can be present in an amount from 0.1% to 10% byweight of the coating composition. For example, in certain embodimentsthe hydrophilic agents are present in an amount of from 0.1% to 5%, andin other embodiments from 0.1% to 3% by weight of the control-releasingcoat composition.

The AQ control-releasing coat formulation also comprises a poly gycolwith a melting point of greater than 55° C. Non-limiting examples of thepolyglycol include polyethylene glycol 6000, polyethylene glycol 8000,polyethylene glycol 10000, polyethylene glycol 20000, and mixturesthereof. In at least one embodiment, the poly glycol is polyethyleneglycol 8000. The poly glycol can be present in an amount of from 0.1% to5% by weight of the coat. Other examples of suitable polyglycolderivatives having a melting point of at least 55° C. include, but arenot limited to, Poloxamer 188, Poloxamer 338, Poloxamer 407,Polyethylene Oxides, Polyoxyethylene Alkyl Ethers, and PolyoxyethyleneStearates.

In addition to the copolymers and the poly glycol, the AQcontrol-releasing coat formulation comprises at least onepharmaceutically acceptable excipient. The excipients can include butare not limited to anti-tacking agents, emulsifying agents, antifoamingagents, flavourants, colourants, etc. It is known in the art thatdepending on the intended main function, excipients can affect theproperties of the coat in a series of ways, and many substances used incoat formulations can thus be described as multifunctional. A skilledworker will know, based on his technical knowledge, whichpharmaceutically acceptable excipients are suitable for the desired AQcontrol releasing coat composition.

The tackiness of polymeric films is a factor for the coating of soliddosage forms and for the subsequent curing step (post coating thermaltreatment). During coating with either cellulosic or acrylic polymers,sometimes an unwanted, and in other times irreversible agglomeration ofseveral granules or beads or, in the worst case, of the complete batch,can occur, especially at higher product processing temperatures.Accordingly, the addition of anti-tacking agents to coating formulationscan be desirable. The anti-tacking agents which can be used include butare not limited to adipic acid, magnesium stearate, calcium stearate,zinc stearate, hydrogenated vegetable oils, sterotex, glycerylmonostearate, talc, sodium benzoate, sodium lauryl sulfate, magnesiumlauryl sulfate, and mixtures thereof. In at least one embodiment, talcis the anti-tacking agent. Talc can also function as a wetting agent.Mixtures of the anti-tacking agents are operable. The amount ofanti-tacking agent in the control-releasing coat composition can be inthe range from 1% to 15% by weight of the control-releasing coatingdispersion. For example, in certain embodiments the anti-tacking agentis present in an amount of from 1% to 7% by weight of thecontrol-releasing coating dispersion.

The anti-foaming agents, which can be included in the AQcontrol-releasing coat composition include silicon oil, simethicone, andmixtures thereof. In at least one embodiment, simethicone is theanti-foaming agent. The anti-foaming agent can be present in an amountof up to 0.5% by weight of the AQ control-releasing coat composition.For example, in certain embodiment the anti-foaming agent is present inan amount of from 0.1% to 0.4% by weight of the AQ control-releasingcoat composition.

The emulsifying agent(s) (also called emulsifiers or emulgents) can beincluded to facilitate emulsification during manufacture of the AQcontrol-releasing coat, and also to provide emulsion stability duringthe shelf-life of the product. Non-limiting examples of emulsifyingagents include naturally occurring materials and their semi syntheticderivatives, such as the polysaccharides, as well as glycerol esters,cellulose ethers, sorbitan esters and polysorbates. Mixtures areoperable. In at least one embodiment the emulsifying agent isPolysorbate 80 (polyoxyethylene sorbitan mono-oleate)(TWEEN™ 80). Theemulsifying agent(s) can be present in an amount of up to 0.5% by weightof the AQ control-releasing coat composition. For example, in certainembodiments the emulsifying agent(s) are present in an amount of from0.1% to 0.3% by weight of the AQ control-releasing coat composition.

Colorants in the film coat formula can be water-insoluble colors(pigments). Pigments have certain advantages over water-soluble colorsin that they tend to be more chemically stable towards light, providebetter opacity and covering power, and optimize the impermeability of agiven film to water vapor. Non-limiting examples of suitable colorantsinclude iron oxide pigments, titanium dioxide, and aluminum Lakes.Mixtures are operable. In at least one embodiment the pigment istitanium dioxide. The pigment or colorant can be present in an amount offrom 0.1% to 10% by weight of the AQ control-releasing coat composition.For example, in certain embodiments the pigment or colorant is presentin an amount of from 0.1% to 5%, and in other embodiments from 0.1% to2% by weight of the AQ control-releasing coat composition.

The AQ control-releasing coat can be applied onto a core comprising aneffective amount of the bupropion salt by a process, which involves theatomization (spraying) of the coating solution or suspension onto a bedof the tablet cores. Some examples of equipment suitable for filmcoating include: Accela Cota (Manesty Machines, Liverpool, UK),Hi-Coater (Freund Company, Japan), Driacoater (Driam Metallprodukt GmbH,Germany), HTF/150 (GS, Italy), and IDA (Dumoulin, France). Examples ofunits that function on a fluidized-bed principle include: Aeromatic(Fielder, Switzerland and UK) and Glatt AG (Switzerland). In at leastone embodiment, the apparatus used for film coating is the Accela Cota.

The coating fluid can be delivered to the coating apparatus from aperistaltic pump at the desired rate and sprayed onto the rotating orfluidizing tablet cores. The tablet cores are pre-warmed to 30° C.During the coating process, the product temperature range is maintainedbetween 25° C. and 35° C. by adjusting the flow rate of the inlet andoutlet air, temperature of the inlet air and spray rate. A single layerof coat is applied and once spraying is complete, the coated tabletcores are dried between 30° C. to 40° C. for 3-5 minutes at a low panspeed and low air flow. The pan is readjusted to jog speed, and dryingcontinues for 12-15 minutes.

The coated tablet cores are placed onto a tray and cured (post coatingthermal treatment) in an electrical or steam oven at a temperature abovethe temperature of the melting point of the polyethylene glycol orderivative thereof. The curing temperature is preferably greater thanthe melting point of the polyethylene glycol or derivative thereof. Thecuring time is preferably 2 to 7 hours. The cured coated tablets aresubsequently cooled to room temperature.

The AQ control-releasing coat is quite versatile. The length and timefor the delay can be controlled by rate of hydration and the thicknessof the coat. The drug release rate subsequent to the delay can bedetermined by the thickness and permeability of the hydrated coat. Thus,it is possible to regulate the rate of hydration and permeability of theAQ control-releasing coat so that the desired controlled-release drugprofile can be achieved. There is no preferred coat thickness, as thiswill depend on the controlled release profile desired. Other parametersin combination with the thickness of the coat include varying theconcentrations of some of the ingredients of the stable coat compositionof the invention described and/or varying the curing temperature andlength of curing the coated tablet cores. The skilled artisan will knowwhich parameters or combination of parameters to change for a desiredcontrolled release profile.

The Moisture Barrier Coat

In certain embodiments, an optional moisture barrier is applied directlyonto the control-releasing coat. In other embodiments a moisture barriercoat is not included in the dosage form. The moisture barrier typicallycomprises an enteric polymer (e.g. acrylic polymer), a permeationenhancer and optionally a plasticizer.

In certain embodiments, the enteric polymer is an acrylic polymer. Forexample, the acrylic polymer can be a methacrylic acid copolymer type C[poly(methacrylic acid, methyl methacrylate) 1:1] available commerciallyunder the trade name EUDRAGIT® (e.g. Eudragit L 30 D-55). Themethacrylic acid copolymer can be present in an amount, which can varyfrom 1% to 3% of the tablet dry weight and from 55% to 70% of themoisture barrier dry weight. For the 174 mg dose of the extended releasetablet of the present invention, the methacrylic acid copolymer can varyfrom 2% to 3% of the tablet dry weight. For example in certainembodiments, the amount of the methacrylic acid copolymer is present at2.5% of the tablet dry weight. With respect to the moisture barrieritself, the amount of the methacrylic acid copolymer can be present inan amount of from 55% to 70% by weight of the moisture barrier dryweight. For example, in certain embodiments the methacrylic acidcopolymer is present in an amount of 60% of the moisture barrier dryweight. For the 348 mg dose of the extended release tablet of thepresent invention, the amount of the methacrylic acid copolymer can varyfrom 1.5% to 3% of the tablet dry weight. For example, in certainembodiments, the amount of methacrylic acid copolymer is present at 2%by weight of the tablet dry weight. With respect to the coating itself,the methacrylic acid copolymer typically will be present in an amount offrom 55% to 70% of the moisture barrier dry weight. For example, incertain embodiments the methacrylic acid copolymer is present in anamount of 60% of the moisture barrier dry weight.

It is known in the art that methacrylic acid copolymers can becomebrittle, and that coatings that contain methacrylic acid copolymerscould be made more elastic and pliable by the addition of a plasticizer.In certain embodiments the moisture barrier coat comprises aplasticizer. Non-limiting examples of plasticizers useful for themoisture barrier coat described herein include acetylatedmonoglycerides; acetyltributyl citrate, butyl phthalyl butyl glycolate;dibutyl tartrate; diethyl phthalate; dimethyl phthalate; ethyl phthalylethyl glycolate; glycerin; propylene glycol; triacetin; tripropioin;diacetin; dibutyl phthalate; acetyl monoglyceride; acetyltriethylcitrate, polyethylene glycols; castor oil; rape seed oil, olive oil,sesame oil, triethyl citrate; polyhydric alcohols, glycerol, glycerinsorbitol, acetate esters, gylcerol triacetate, acetyl triethyl citrate,dibenzyl phthalate, dihexyl phthalate, butyl octyl phthalate, diisononylphthalate, butyl octyl phthalate, dioctyl azelate, epoxidized tallate,triisoctyl trimellitate, diethylhexyl phthalate, di-n-octyl phthalate,di-i-octyl phthalate, di-i-decyl phthalate, di-n-undecyl phthalate,di-n-tridecyl phthalate, tri-2-ethylhexyl trimellitate, di-2-ethylhexyladipate, di-2-ethylhexyl sebacate, di-2-ethylhexyl azelate, dibutylsebacate, diethyloxalate, diethylmalate, diethylfumerate,dibutylsuccinate, diethylmalonate, dibutylphthalate, dibutylsebacate,glyceroltributyrate, and mixtures thereof, polyols (e.g. polyethyleneglycol) of various molecular weights, and mixtures thereof. In certainembodiments, the plasticizer in the moisture barrier coat comprises acombination of triethyl citrate and polyethylene glycol 4000 (e.g.CARBOWAX® 4000). In certain of these embodiments, the ratio of triethylcitrate to polyethylene glycol 4000 is 1:2. The plasticizer can bepresent in an amount which can vary from 0.2% to 0.5%. For example, incertain embodiments the plasticizer is present in an amount of from 0.2%to 0.4% of the tablet dry weight. The plasticizer can be present in anamount of 0.35% of the tablet dry weight for a 174 mg tablet; and in anamount of from 0.2% to 0.4% of the tablet dry weight for a 348 mgtablet. With respect to the moisture barrier itself, the plasticizer ifpresent typically can be present in an amount of from 1% to 30% byweight of the moisture barrier dry weight. For example, in certainembodiments the plasticizer is present in an amount of from 10% to 14%of the moisture barrier dry weight for both the 174 mg and 348 mg doseextended release tablet of the present invention. It is well known inthe art that depending on the intended main function, excipients to beused in tablets are subcategorized into different groups. However, oneexcipient can affect the properties of a drug or the tablet as a wholein a series of ways, and many substances used in tablet formulations cantherefore be described as multifunctional. Thus, the polyethylene glycolused in the plasticizer combination for the moisture barrier can servenot only to increase the hydrophilicity of the moisture barrier, but canalso act as a glidant.

The moisture barrier further may comprise a permeation enhancer that canincrease its hydrophilicity, and can also act as a glidant. Thepermeation enhancer can be a hydrophilic substance and can be selectedfrom the following: hydrophilic polymers such ashydroxypropylmethylcellulose, cellulose ethers and protein-derivedmaterials of these polymers, the cellulose ethers, especiallyhydroxyalkylcelluloses and carboxyalkylcelluloses, are preferred. Also,synthetic water-soluble polymers can be used, such aspolyvinylpyrrolidone, cross-linked polyvinyl-pyrrolidone, polyethyleneoxide, etc., water-soluble polydextrose, saccharides andpolysaccharides, such as pullulan, dextran, sucrose, glucose, lactose,fructose, mannitol, mannose, galactose, sorbitol and the like. In atleast one embodiment of the present invention, the hydrophilic polymercomprises hydroxypropyl-methylcellulose. Other non-limiting examples ofpermeation enhancers include alkali metal salts such as aluminumoxidelithium carbonate, sodium chloride, sodium bromide, potassiumchloride, potassium sulfate, potassium phosphate, sodium acetate, sodiumcitrate, and the like. The pore-forming solids can also be polymerswhich are soluble in the environment of use, such as CARBOWAXES®,CARBOPOL®, and the like. The pore-formers embrace diols, polyols,polyhydric alcohols, polyalkylene glycols, polyglycols,poly(a-w)alkylenediols, and the like. Other permeation enhancers whichcan be useful in the formulations of the present invention includestarch, modified starch, and starch derivatives, gums, including but notlimited to xanthan gum, alginic acid, other alginates, benitonite,veegum, agar, guar, locust bean gum, gum arabic, quince psyllium, flaxseed, okra gum, arabinoglactin, pectin, tragacanth, scleroglucan,dextran, amylose, amylopectin, dextrin, etc., cross-linkedpolyvinylpyrrolidone, ion-exchange resins, such as potassiumpolymethacrylate, carrageenan, kappa-carrageenan, lambda-carrageenan,gum karaya, biosynthetic gum, etc. Other pore-formers include materialsuseful for making microporous lamina in the environment of use, such aspolycarbonates comprised of linear polyesters of carbonic acid in whichcarbonate groups reoccur in the polymer chain, microporous materialssuch as bisphenol, a microporous poly(vinylchloride), micro-porouspolyamides, microporous modacrylic copolymers, microporousstyrene-acrylic and its copolymers, porous polysulfones, halogenatedpoly(vinylidene), polychloroethers, acetal polymers, polyesters preparedby esterification of a dicarboxylic acid or anhydride with an alkylenepolyol, poly(alkylenesulfides), phenolics, polyesters, asymmetric porouspolymers, cross-linked olefin polymers, hydrophilic microporoushiomopolymers, copolymers or interpolymers having a reduced bulkdensity, and other similar materials, poly(urethane), cross-linkedchain-extended poly(urethane), poly(imides), poly(benzimidazoles),collodion, regenerated proteins, semi-solid cross-linkedpoly(vinylpyrrolidone), silicon dioxide, colloidal silica,microcrystalline cellulose and any combination thereof. In at least oneembodiment of the invention the permeation enhancer is silicon doxide(e.g. SYLOID® 244FP). The amount of permeation enhancer can vary from0.5% to 1% by weight of the tablet dry weight and from 25% to 30% byweight of the moisture barrier dry weight. For the 174 mg doseextended-release tablet of the invention, the permeation enhancer can bepresent in an amount of 0.5% to 2% of the tablet dry weight, and from20% to 40% by weight of the moisture barrier dry weight. For example, incertain embodiments of the 174 mg dose tablet, the permeation enhanceris present in an amount of from 25% to 30% by weight of the moisturebarrier dry weight. For the 348 mg dose extended release tablet of theinvention, the permeation enhancer can be present in an amount which canvary from 0.5% to 2% by weight of the tablet dry weight, and from 20% to40% by weight of the moisture barrier dry weight. For example, incertain embodiments of the 348 mg dose tablet, the permeation enhanceris present in an amount of from 25% to 30% by weight of the moisturebarrier dry weight.

In at least one embodiment of the invention, the ratio of themethacrylic acid copolymer:plasticizer:permeation enhancer is 13:2:5.

The preparation and application of the moisture barrier process can beas follows. The optional plasticizer (e.g. a combination of polyethyleneglycol 4000 and triethyl citrate), can be first added to water and themixture mixed to homogeneity. The methacrylic acid copolymer (e.g.EUDRAGIT® L 30 D-55), is next sieved and added to the plasticizermixture and mixed to homogeneity. In a separate container the permeationenhancer (e.g. silicon dioxide) is dissolved in water until ahomogeneous mixture is achieved. The plasticizer and methacrylic acidcopolymer mixture is then combined with the permeation enhancer solutionand mixed to homogeneity. The resulting moisture barrier solution isthen sprayed onto the tablet cores coated with the control-releasingcoat using a tablet coater, fluidized bed apparatus or any othersuitable coating apparatus known in the art until the desired weightgain is achieved. The tablets coated with the moisture barrier aresubsequently dried prior to packaging.

The moisture barrier is applied to the control-releasing coated tabletcores such that the weight gain is not more than 6% of the tablet dryweight for both the 174 mg and 348 mg extended release tablets of thepresent invention. In at least one embodiment the weight gain is notmore than 3.5% of the tablet dry weight for both 174 mg and 348 mgextended release tablets according to the present invention. The amountof the moisture barrier applied typically does not significantly renderthe extended release tablet described herein more resistant to gastricfluid. However, the moisture barrier can have an impact on the drugrelease characteristics.

The moisture barrier as used herein if present in the bupropionhydrobromide medicament typically does not function as an enteric coat.Even though the methacrylic acid copolymer, EUDRAGIT® L 30 D-55, isreferenced and is used in enteric coating formulations in the art, itsfunctionality is formulation dependent and on the quantity of thematerial applied. As is known in the art, an enteric coating is appliedwhere a drug may be destroyed or inactivated by gastric juice or wherethe drug may irritate the gastric mucosa. To meet the requirements foran enteric coat, the test as described in the USP (method A or B)stipulates that after 2 hours in acidic media (0.1N HCl), no individualvalues of at least six experiments exceed 10% of the active drugdissolved and not less than 75% dissolved at 45 minutes in pH 6.8. Themoisture barrier typically does not meet this requirement for thefollowing reasons even though the bupropion salt (e.g. bupropionhydrobromide) is not negatively affected in acidic media nor is itirritating the gastric mucosa: (1) to obtain enteric integrity with afilm containing EUDRAGIT® L 30 D-55, a weight gain of between 6% to 8%based on the dry polymer per dosage unit is recommended. The amount ofEUDRAGIT® L 30 D-55 solid applied onto the control-releasing coatedtablet cores is not more than 6%, and in at least one embodiment, is notmore than 3%, (2) if enteric integrity would be required, thedissolution test for the finished product (i.e., the moisture barriercoated tablet cores) at the 2 hour time point would not stipulate alimit of no more than 20%, and (3) analytical tests performed on thesecoatings indicate that the coatings do not meet all the testrequirements as an enteric coated product as defined by USP testmethods.

The XL tablet of the invention provides an extended release of thebupropion salt. Generally no pore forming agent is present in the XLcoating formulation. An extended release bupropion hydrobromideformulation is provided such that after 2 hours, not more than 20% ofthe bupropion hydrobromide content is released. For example, in certainembodiments, from 2% to 18%, from 4% to 8%, or 5% of the bupropionhydrobromide content is released after 2 hours. After 4 hours, from 15%to 45% of the bupropion hydrobromide content is released. For example,in certain embodiments from 21% to 37%, from 28% to 34%, or 32% of thebupropion hydrobromide content is released after 4 hours. After 8 hours,40% to 90% of the bupropion hydrobromide content is released. Forexample, in certain embodiments from 60% to 85%, from 68% to 74%, or 74%of the bupropion hydrobromide content is released after 8 hours. After16 hours not less than 80% of the bupropion hydrobromide content isreleased. For example, in certain embodiments not less than 93%, notless than 96%, or not less than 99% of the bupropion hydrobromidecontent is released.

Also, extended release tablets are provided wherein after 2 hours notmore than 40% (e.g., 33%) of the bupropion hydromide is released; after4 hours from 40-75% of the bupropion hydrobromide is released (e.g.,59%); after 8 hours at least 75% of the bupropion hydrobromide isreleased (e.g., 91%); and after 16 hours at least 85% of the bupropionhydrobromide is released (e.g., 97%). In all instances herein whenactual or prophetic dissolution profiles are provided this means thatthe medicament possesses such a profile in at least one dissolutionmedium under prescribed conditions such as are identified herein and arewell known to those skilled in the art. Such dissolution media,dissolution conditions and apparatus for use therein are disclosed inthe United States Pharmacopoeia (USP) and European and Japanesecounterparts thereof. Additionally, specific examples thereof areprovided in this application.

Enhanced Absorption (EA) Tablets

In another aspect of the present invention, there is provided anenhanced absorption (EA) tablet having a core comprising apharmaceutically acceptable salt of bupropion and conventionalexcipients, wherein the bupropion salt is more stable than bupropionhydrochloride such as bupropion hydrobromide. The core is surrounded byan EA coating, which controls the release of the bupropion salt. Incertain embodiments, the EA coating consists of one coat. An advantageof the EA tablet includes the lessening of the amount of drug requiredin the composition, which in turn can lead to a reduction of sideeffects. The EA tablet of the invention has unexpected enhancedstability.

The EA Core

The core of the EA tablet comprises an effective amount of a bupropionsalt, a binder and a lubricant, and can contain other conventional inertexcipients. The amount of the bupropion salt present in the EA core canvary from 40% to 99% by weight of the tablet dry weight. For example, incertain embodiments bupropion hydrobromide is present in an amount offrom 50% to 95%, and in other embodiments in an amount of from 70% to90% by weight of the tablet dry weight. The tablet comprises aneffective amount of bupropion salt that can vary from 50 mg to 450 mg.For example, the EA tablet can comprise 150 mg or 300 mg of bupropionhydrobromide. For a 150 mg dose tablet the bupropion hydrobromide can bepresent in an amount of from 76% to 84% by weight of the tablet dryweight. For a 300 mg dose, the amount of bupropion hydrobromide can bepresent in an amount of from 80% to 83% by weight of the tablet dryweight. For both the 150 mg and 300 mg dose bupropion hydrobromide EAtablets of the invention, the amount of bupropion hydrobromide can bepresent at 94% by weight of the dry core for each dose.

A binder (also sometimes called adhesive) can be added to a drug-fillermixture to increase the mechanical strength of the granules and tabletsduring formation. Binders can be added to the formulation in differentways: (1) as a dry powder, which is mixed with other ingredients beforewet agglomeration, (2) as a solution, which is used as agglomerationliquid during wet agglomeration, and is referred to as a solutionbinder, and (3) as a dry powder, which is mixed with the otheringredients before compaction, (referred to as a dry binder). Solutionbinders are a common way of incorporating a binder into granules. Incertain embodiments, the binder used in the EA tablets is in the form ofa solution binder. Non-limiting examples of binders include hydrogenatedvegetable oil, castor oil, paraffin, higher aliphatic alcohols, higheralphatic acids, long chain fatty acids, fatty acid esters, wax-likematerials such as fatty alcohols, fatty acid esters, fatty acidglycerides, hydrogenated fats, hydrocarbons, normal waxes, stearic acid,stearyl alcohol, hydrophobic and hydrophilic polymers having hydrocarbonbackbones, and mixtures thereof. Specific examples of water-solublepolymer binders include modified starch, gelatin, polyvinylpyrrolidone,cellulose derivatives (such as for example hydroxypropyl methylcellulose(HPMC) and hydroxypropyl cellulose (HPC)), polyvinyl alcohol andmixtures thereof. The amount of binder present can vary from 0.5% to 25%by weight of the tablet dry weight. For example, in certain embodimentsof the invention, the amount of binder present varies from 0.5% to 15%by weight of the tablet dry weight; in other embodiments from 1% to 6%by weight of the tablet dry weight; and in still other embodiments 3% byweight of the tablet dry weight. For both the 150 mg and 300 mg dose EAtablets, the amount of binder can be present in an amount of from 1% to6% by weight of each dry core weight. For example, in certainembodiments the amount of binder is present in an amount of 3% by weightof each dry core weight. In at least one embodiment of the invention thebinder is polyvinyl alcohol.

Lubricants can be added to pharmaceutical formulations to decrease anyfriction that occurs between the solid and the die wall during tabletmanufacturing. High friction during tabletting can cause a series ofproblems, including inadequate tablet quality (capping or evenfragmentation of tablets during ejection, and vertical scratches ontablet edges) and may even stop production. Accordingly, lubricants canbe added to certain tablet formulations of the present inventionincluding the EA tablet formulation described herein. Non-limitingexamples of lubricants useful for the EA core include glyceryl behenate,stearic acid, hydrogenated vegetable oils (such as hydrogenatedcottonseed oil (STEROTEX®), hydrogenated soybean oil (STEROTEX® HM) andhydrogenated soybean oil & castor wax (STEROTEX® K), stearyl alcohol,leucine, polyethylene glycol (MW 1450, suitably 4000, and higher),magnesium stearate, glyceryl monostearate, stearic acid, polyethyleneglycol, ethylene oxide polymers (for example, available under theregistered trademark CARBOWAX® from Union Carbide, Inc., Danbury,Conn.), sodium lauryl sulfate, magnesium lauryl sulfate, sodium oleate,sodium stearyl fumarate, DL-leucine, colloidal silica, and others asknown in the art. In at least one embodiment of the invention, thelubricant is glyceryl behenate (e.g. COMPRITOL® 888). The amount oflubricant present can vary from 0.1% to 6% by weight of the tablet dryweight. For example, in certain embodiments the amount of lubricantpresent is 3% by weight of the tablet dry weight. For certainembodiments of the 174 mg and 348 mg dose EA tablets of the inventionthe lubricant is present in an amount of 3% by weight of the tablet dryweight and from 1% to 6% by weight of the dry core weight. For example,in certain embodiments the lubricant is present in an amount of 3% byweight of the dry core weight for both the 174 mg and 348 mg dose EAtablets.

At this stage, the EA core formulation is an uncoated immediate releaseformulation resulting in 100% dissolution of the bupropion salt within 1hour. In at least one embodiment the EA core is a normal release matrixformulation. In certain embodiments the core comprises an effectiveamount of bupropion hydrobromide, a binder (e.g. polyvinyl alcohol), anda lubricant (e.g. glyceryl behenate). However, if necessary, additionalinert excipients consistent with the objects of the invention can beadded to the core formulation. The additional inert excipients can beadded to facilitate the preparation and/or improve patient acceptabilityof the final EA bupropion salt dosage form as described herein. Theadditional inert excipients are well known to the skilled artisan andcan be found in the relevant literature, for example in the Handbook ofPharmaceutical Excipients. Non-limiting examples of such excipientsinclude spray dried lactose, sorbitol, mannitol, and any cellulosederivative.

In certain embodiments, the granules to be compressed to form the coreof the EA tablet of the invention described herein are manufactured bythe wet granulation process. Wet granulation involves agitation of apowder (the active drug) by convention in the presence of a liquid (thesolution binder) followed by drying. For forming the granules, which areto be eventually compressed into the tablet cores, the bupropion salt isfirst granulated, for example with a solution binder, in a granulator,for example a fluidized bed granulator such as a fluidized bedgranulator manufactured by Glatt (Germany) or Aeromatic (Switzerland).The binder (e.g. polyvinyl alcohol) is first dissolved or dispersed in asuitable solvent (e.g. water). The solution binder is then top sprayedonto the drug in a granulator (e.g. a fluidized bed granulator).Alternatively, granulation can also be performed in a conventional orhigh shear mixer. If necessary, the additional inert excipients (e.g. afiller) can be mixed with the bupropion salt prior to the granulationstep.

The granules formed are subsequently dried and then sieved prior toblending the granules with the lubricant. In certain embodiments thedried granules are sieved through a 1.4 mm mesh screen. The sievedgranules are then blended with the lubricant, and if necessary, anyother additional inert excipients, which can improve processing of theEA tablets of the invention. Blending of the granules with thelubricant, and if necessary, any additional inert excipients, such asfor example a glidant, can be performed in a V-blender or any othersuitable blending apparatus. Glidants can improve the flowability of thepowder. This is especially important during tablet production at highproduction speeds and during direct compaction. However, because therequirement for adequate flow is high, a glidant is often also added toa granulation before tabletting. The blended granules are subsequentlypressed into tablets and are hereinafter referred to as tablet cores.Tablet cores can be obtained by the use of standard techniques andequipment well known to the skilled artisan. In certain embodiments thetablet cores are obtained by a rotary press (also referred to as amulti-station press) fitted with suitable punches.

The granules can also be manufactured by using other processes known tothe skilled artisan. Examples of other granule manufacturing processesinclude dry granulation (e.g. slugging, roller compaction), directcompression, extrusion, spheronization, melt granulation, and rotarygranulation.

An example of the granulation process for the EA cores (60 kg batch) isas follows: A Fluid Bed Processor is used for granulation in order toagglomerate the particles of the materials to obtain a uniform particlesize for the final blend. The granulating solution is prepared bydissolving the binder (e.g. polyvinyl alcohol) in hot purified waterwhile mixing. The percent solids content can be adjusted to obtain aviscosity to control the build up (agglomeration size) of the material.A lower viscosity leads to smaller particles, and a higher viscosityleads to larger particles. In addition, the application rate (e.g. from150 gm/min to 250 gm/min; or 200 gm/min), position of Spray gun (e.g.center position) and nozzle size (e.g. from 0.5 mm to 2 mm; or 1 mm) andatomization pressure (e.g. from 20 psi to 40 psi; or 30 psi) contributefurther to control particle size. The active material is fluidized andheated (e.g. from 35° C. to 45° C.; or 40° C.) prior to start ofsolution application. During the spray cycle, the bed temperature (e.g.from 35° C. to 45° C.; or 40° C.) is kept at a constant temperature toavoid over-wetting. Once all the required binder solution is applied,the material is further dried to the targeted LOD value (i.e. loss ondrying) (e.g. below 1%) prior to unloading. The amount of binder (e.g.polyvinyl alcohol) is between 2% to 6%, and in some cases 3%; and thesolution concentration is between 3% to 7%, and in some cases 4.5%. Thetime of agglomeration process for the 60 kg batch is between 45 minutesto 220 minutes, and in some cases 150 minutes. Once the granulate isdry, material is passed through a 1.4 and 2.00 mm screen to remove anyoversized particles. The oversize particles are passed through the millto reduce oversize particles. Oversized particles generally not toexceed 5% of total yield. The screened and milled materials are placedinto a shell blender (e.g. V-Blender, Bin blender) and the lubricant(e.g. glyceryl behenate) is added. The lubricant is screened and addedto the granules and blended at the predetermined number of revolutionsor time (e.g. mix time of 5 min to 15 min, and in some cases 10 min).The percent lubricant is between 0.5% to 4%, and in some cases 2%. Thelevel of lubrication is established for sufficient coverage of eitherlarger or smaller particle size distribution. Additional characteristicsinclude bulk density (e.g. from 0.3 gm/ml to 0.8 gm/ml, and in somecases 0.5 gm/ml), and moisture content (e.g. not more than 1%). Particlesize and flow of final blend are factors in obtaining uniform fill ofcavities on a rotary press. The flow and top rotation speed of the pressare adjusted (dependant on the type/size of press) so as to notjeopardize the weight uniformity of individual tablets. The productblend is passed through a hopper into a feed frame to fill the diecavities passing under the feed frame. Weight adjustments are made tokeep the weight within the specified range, and adjustments made to thepressure settings to obtain the required hardness. Some componentsmonitored for the tablets are tablet thickness and friability (e.g. lessthan 0.5%). Suitable thickness (related to overall surface area) andlower friability help reduce core damage and loss of active duringcoating. Tablet samples are removed at predetermined intervals tomonitor specifications.

The EA Tablet Coating

The EA tablet cores can be coated in one stage. The EA coating isapplied directly onto the surface of the tablet cores and functions tocontrol the release of the bupropion salt.

The EA coating is a semi-permeable coat comprising a water-insoluble,water-permeable film-forming polymer, a water-soluble polymer, andoptionally a plasticizer.

Non-limiting examples of water-insoluble, water-permeable film-formingpolymers useful for the EA coating include cellulose ethers, celluloseesters, polyvinyl alcohol and mixtures thereof. In certain embodiments,the water-insoluble, water-permeable film forming polymers are the ethylcelluloses, and can be selected from the following: ethyl cellulosegrades PR100, PR45PR20, PR10 and PR7 (ETHOCEL®, Dow) and combinationsthereof. In at least one embodiment ethyl cellulose grade PR 100 is thewater-insoluble, water-permeable film-forming polymer. The amount of thewater-insoluble water-permeable film-forming polymer can vary from 1% to8% by weight of the tablet dry weight. For example, in certainembodiments the amount of the water-insoluble water-permeablefilm-forming polymer is from 2% to 6% by weight of the tablet dryweight. For certain embodiments of the 174 or 348 mg dose EA tablets ofthe invention, the amount of water-insoluble water permeablefilm-forming polymer is from 1% to 15% by weight of the tablet dryweight. For example, in certain embodiments of the 174 mg dose EAtablets, the amount of the water-insoluble water-permeable film-formingpolymer is present at 10.5% by weight of the tablet dry weight. Withrespect to the EA coat itself, the amount of water-insolublewater-permeable film-forming polymer in certain embodiments of the 174mg dose EA tablets is from 35% to 60% by weight of the EA coat dryweight. For example, in certain embodiments of the 174 mg dose EAtablet, the amount of water-insoluble water-permeable polymer is presentat 55% by weight of the EA coat dry weight. For certain embodiments ofthe 348 mg dose EA tablet of the invention, the amount ofwater-insoluble water-permeable film-forming polymer is from 1% to 8% byweight of the tablet dry weight. For example, in certain embodiments ofthe 300 mg dose EA tablet, the amount of water-insoluble water-permeablefilm forming polymer is present at 6.3% by weight of the tablet dryweight. With respect to the EA coat itself, the water-insolublewater-permeable film-forming polymer in the 300 mg dose EA tablet can bepresent in an amount of 55% by weight of the EA coat dry weight.

In certain embodiments, the EA coat further comprises a plasticizer.Non-limiting examples of plasticizers that can be used in the EA coatdescribed herein include acetylated monoglycerides; acetyltributylcitrate, butyl phthalyl butyl glycolate; dibutyl tartrate; diethylphthalate; dimethyl phthalate; ethyl phthalyl ethyl glycolate; glycerin;propylene glycol; triacetin; tripropioin; diacetin; dibutyl phthalate;acetyl monoglyceride; acetyltriethyl citrate, polyethylene glycols;castor oil; rape seed oil, olive oil, sesame oil, triethyl citrate;polyhydric alcohols, glycerol, glycerin sorbitol, acetate esters,gylcerol triacetate, acetyl triethyl citrate, dibenzyl phthalate,dihexyl phthalate, butyl octyl phthalate, diisononyl phthalate, butyloctyl phthalate, dioctyl azelate, epoxidized tallate, triisoctyltrimellitate, diethylhexyl phthalate, di-n-octyl phthalate, di-i-octylphthalate, di-i-decyl phthalate, di-n-undecyl phthalate, di-n-tridecylphthalate, tri-2-ethylhexyl trimellitate, di-2-ethylhexyl adipate,di-2-ethylhexyl sebacate, di-2-ethylhexyl azelate, dibutyl sebacate,diethyloxalate, diethylmalate, diethylfumerate, dibutylsuccinate,diethylmalonate, dibutylphthalate, dibutylsebacate, glyceroltributyrate,and mixtures thereof, polyols (e.g. polyethylene glycol) of variousmolecular weights, and mixtures thereof. The amount of plasticizer forthe EA coat can vary in an amount from 0.5% to 4% by weight of thetablet dry weight. In a further embodiment of the invention, when amixture of two plasticizers are used, the ratio of the two plasticizerscan range from 5:95 to 95:5. In at least one embodiment of theinvention, the plasticizer is polyethylene glycol 4000, dibutylsebacate, or a mixture thereof. The ratio of polyethylene glycol4000:dibutyl sebacate can range from 5:95 to 95:5. For certainembodiments of the 174 mg dose EA tablet of the invention, the amount ofplasticizer present in the EA coat is from 0.5% to 4% by weight of thetablet dry weight. For example, in certain embodiments of the 174 mgdose EA tablet, the amount of plasticizer is present at 3.1% by weightof the tablet dry weight. For certain embodiments of the 348 mg dose EAtablet of the invention, the amount of plasticizer present is from 0.5%to 3% by weight of the tablet dry weight. For example, in certainembodiments of the 348 mg dose EA tablet, the amount of plasticizer ispresent at 2.0% by weight of the tablet dry weight. For certainembodiments of both the 174 mg and 348 mg dosage forms, the plasticizeris present in an amount of from 6% to 30% by weight of the EA coat dryweight. For example, in certain embodiments the amount of plasticizer ispresent at 17% by weight of the EA coat dry weight.

Non-limiting examples of water-soluble polymers useful for the EA coatinclude polyvinylpyrrolidone, hydroxypropyl methylcellulose,hydroxypropyl cellulose and mixtures thereof. In at least one embodimentof the invention, the water-soluble polymer is polyvinylpyrrolidone(e.g. POVIDONE® USP) the amount of which can vary from 1.5% to 10% byweight of the tablet dry weight. With respect to the EA coat itself, theamount of water-soluble polymer present can vary from 20% to 50% byweight of the EA coat dry weight. For certain embodiments of the 174 mgdose of the EA tablet of the invention, the amount of water-solublepolymer present is from 1.5% to 10% by weight of the tablet dry weightor from 20% to 50% by weight of the EA coat dry weight. For example, incertain embodiments of the 174 mg dose EA tablet, the water-solublepolymer is present in an amount of 28% by weight of the EA coat dryweight. For certain embodiments of the 348 mg dose of the EA tablet ofthe invention, the amount of water-soluble polymer present is from 1.5%to 10% of the tablet dry weight and from 20% to 50% by weight of the EAcoat dry weight. For example, in certain embodiments of the 300 mg doseEA tablet, the water-soluble polymer is present in an amount of 28% byweight of the EA coat dry weight.

The ratio of water-insoluble water-permeable film formingpolymer:plasticizer:water-soluble polymer for the EA tablet coatingtypically will vary from 3:1:4 to 5:1:2. For example in certainembodiments the ratio of water-insoluble water-permeable film formingpolymer:plasticizer:water-soluble polymer for the EA tablet coating is4:1:3. In at least one embodiment of the EA tablet coating, the ratio ofthe water-insoluble water-impermeable film-formingpolymer:plasticizer:water-soluble polymer is from 7:2:6 to 19:5:18, andin other embodiments is 13:4:12.

Preparation and application of the EA coat can be as follows. Thewater-insoluble water-permeable film-forming polymer, (e.g.ethylcellulose), and the plasticizer (e.g. polyethylene glycol 4000,dibutyl sebacate, or a mixture thereof), are dissolved in an organicsolvent (e.g. ethyl alcohol). The water-soluble polymer (e.g. polyvinylpyrrolidone) is next added until a homogenous mixture is achieved. Theresulting control-releasing coat solution is then sprayed onto thetablet cores using a tablet coater, fluidized bed apparatus or any othersuitable coating apparatus known in the art until the desired weightgain is achieved. The tablet cores coated with the EA coat aresubsequently dried before a moisture barricr is applied.

The skilled artisan will appreciate that controlling the permeabilitycan control the release of the bupropion salt and/or the amount ofcoating applied to the tablet cores. The permeability of the EA coat canbe altered by varying the ratio of the water-insoluble, water-permeablefilm-forming polymer:plasticizer:water-soluble polymer and/or thequantity of coating applied to the tablet core. A more extended releasecan be obtained with a higher amount of water-insoluble, water-permeablefilm forming polymer. The addition of other excipients to the tabletcore can also alter the permeability of the EA coat. For example, if itis desired that the tablet core further comprise an expanding agent, theamount of plasticizer in the control-releasing coat should be increasedto make the coat more pliable as the pressure exerted on a less pliablecoat by the expanding agent could rupture the coat. Further, theproportion of the water-insoluble water-permeable film forming polymerand water-soluble polymer may also have to be altered depending onwhether a faster or slower dissolution and/or release profile isdesired.

Depending on the dissolution or in-vivo release profile desired, theweight gained after coating the tablet core with the EA coat can varyfrom 3% to 30% of the weight of the dry tablet core. For certainembodiments of the 174 mg dose EA tablet of the invention the weightgain is from 8% to 20% of the weight of the dry tablet core. Forexample, in certain embodiments of the 174 mg dose EA tablet, the weightgain is 14% of the weight of the dry tablet core. For certainembodiments of the 348 mg dose EA tablet of the invention the weightgain is from 10% to 15% of the weight of the dry tablet core. Forexample, in certain embodiments of the 348 mg dose EA tablet, the weightgain is 13% of the weight of the dry tablet core.

The EA tablet of the invention provides an enhanced-absorption of thebupropion salt wherein typically no pore forming agent is present in theformulation. An enhanced absorption bupropion hydrobromide formulationis provided such that after 2 hours, not more than 25% of the bupropionhydrobromide content is released. For example, in certain embodimentsfrom 10% to 20% of the bupropion hydrobromide content is released after2 hours. After 4 hours, 25% to 55% of the bupropion hydrobromide contentis released. For example, in certain embodiments from 30% to 50% of thebupropion hydrobromide content is released after 4 hours. After 8 hours,more than 60% of the bupropion hydrobromide content is released. Forexample, in certain embodiments from 70% to 90% of the bupropionhydrobromide content is released after 8 hours. After 16 hours more than70% of the bupropion hydrobromide content is released. For example, incertain embodiments more than 80% of the bupropion hydrobromide contentis released after 16 hours.

In addition in some embodiments the invention provides enhancedabsorption formulations wherein not more than 40% is released after 2hours (e.g, 33%); after 4 hours from 40-75% is released (e.g., 59%);after 8 hours at least 75% is released (e.g., 91%); and after 16 hoursat least 85% is released (e.g., 97%).

Controlled Release Matrix

In other embodiments of the present invention, a controlled releasematrix is provided from which the kinetics of drug release from thematrix core are dependent at least in part upon the diffusion and/orerosion properties of excipients within the composition. In thisembodiment controlled release matrices contain an effective amount of abupropion salt and at least one pharmaceutically acceptable excipient.The amount of the bupropion salt present in the controlled releasematrix can vary in an amount of from 40% to 90% by weight of the matrixtablet dry weight. For example, in certain embodiments bupropionhydrobromide is present in an amount from 60% to 80%, and in otherembodiment at 70% by weight of the matrix tablet dry weight. Thecontrolled release matrix can be multiparticulate or uniparticulate, andcan be coated with at least one functional or non-functional coating, oran immediate release coating containing a bupropion salt or other drug.Functional coatings include by way of example controlled releasepolymeric coatings, enteric polymeric coatings, and the like.Non-functional coatings are coatings that do not affect drug release butwhich affect other properties (e.g., they may enhance the chemical,biological, or the physical appearance of the controlled releaseformulation). Those skilled in the pharmaceutical art and the design ofmedicaments are well aware of controlled release matrices conventionallyused in oral pharmaceutical compositions adopted for controlled releaseand means for their preparation. Examples of controlled release matricesare described in U.S. Pat. Nos. 6,326,027; 6,340,475; 6,905,709;6,645,527; 6,576,260; 6,326,027; 6,254,887; 6,306,438; 6,129,933;5,891,471; 5,849,240; 5,965,163; 6,162,467; 5,567,439; 5,552,159;5,510,114; 5,476,528; 5,453,283; 5,443,846; 5,403,593; 5,378,462;5,350,584; 5,283,065; 5,273,758; 5,266,331; 5,202,128; 5,183,690;5,178,868; 5,126,145; 5,073,379; 5,023,089; 5,007,790; 4,970,075;4,959,208; 4,59,208; 4,861,598; 4,844,909; 4,834,984; 4,828,836;4,806,337; 4,801,460; 4,764,378; 4,421,736; 4,344,431; 4,343,789;4,346,709; 4,230,687; 4,132,753; 5,591,452; 5,965,161; 5,958,452;6,254,887; 6,156,342; 5,395,626; 5,474,786; and 5,919,826.

Suitable excipient materials for use in such controlled release matricesinclude, by way of example, release-resistant or controlled releasematerials such as hydrophobic polymers, hydrophilic polymers, lipophilicmaterials and mixtures thereof. Non-limiting examples of hydrophobic, orlipophilic components include glyceryl monostearate, mixtures ofglyceryl monostearate and glyceryl monopalmitate (Myvaplex, Eastman FineChemical Company), glycerylmonooleate, a mixture of mono, di andtri-glycerides (ATMUL 84S), glycerylmonolaurate, paraffin, white wax,long chain carboxylic acids, long chain carboxylic acid esters, longchain carboxylic acid alcohols, and mixtures thereof. The long chaincarboxylic acids can contain from 6 to 30 carbon atoms; in certainembodiments at least 12 carbon atoms, and in other embodiments from 12to 22 carbon atoms. In some embodiments this carbon chain is fullysaturated and unbranched, while others contain one or more double bonds.In at least one embodiment the long chain carboxylic acids contain3-carbon rings or hydroxyl groups. Non-limiting examples of saturatedstraight chain acids include n-dodecanoic acid, n-tetradecanoic acid,n-hexadecanoic acid, caproic acid, caprylic acid, capric acid, lauricacid, myristic acid, palmitic acid, stearic acid, arachidic acid,behenic acid, montanic acid and melissic acid. Also useful areunsaturated monoolefinic straight chain monocarboxylic acids.Non-limiting examples of these include oleic acid, gadoleic acid anderucic acid. Also useful are unsaturated (polyolefinic) straight chainmonocaboxyic acids. Non-limiting examples of these include linoleicacid, linolenic acid, arachidonic acid and behenolic acid. Usefulbranched acids include, for example, diacetyl tartaric acid.Non-limiting examples of long chain carboxylic acid esters includeglyceryl monostearates; glyceryl monopalmitates; mixtures of glycerylmonostearate and glyceryl monopalmitate (Myvaplex 600, Eastman FineChemical Company); glyceryl monolinoleate; glyceryl monooleate; mixturesof glyceryl monopalmitate, glyceryl monostearate glyceryl monooleate andglyceryl monolinoleate (Myverol 18-92, Eastman Fine Chemical Company);glyceryl monolinolenate; glyceryl monogadoleate; mixtures of glycerylmonopalmitate, glyceryl monostearate, glyceryl monooleate, glycerylmonolinoleate, glyceryl monolinolenate and glyceryl monogadolcate(Myverol 18-99, Eastman Fine Chemical Company); acetylated glyceridessuch as distilled acetylated monoglycerides (Myvacet 5-07, 7-07 and9-45, Eastman Fine Chemical Company); mixtures of propylene glycolmonoesters, distilled monoglycerides, sodium stearoyl lactylate andsilicon dioxide (Myvatex TL, Eastman Fine Chemical Company); mixtures ofpropylene glycol monoesters, distilled monoglycerides, sodium stearoyllactylate and silicon dioxide (Myvatex TL, Eastman Fine ChemicalCompany) d-alpha tocopherol polyethylene glycol 1000 succinate (VitaminE TPGS, Eastman Chemical Company); mixtures of mono- and diglycerideesters such as Atmul (Humko Chemical Division of Witco Chemical);calcium stearoyl lactylate; ethoxylated mono- and di-glycerides;lactated mono- and di-glycerides; lactylate carboxylic acid ester ofglycerol and propylene glycol; lactylic esters of long chain carboxylicacids; polyglycerol esters of long chain carboxylic acids, propyleneglycol mono- and di-esters of long chain carboxylic acids; sodiumstearoyl lactylate; sorbitan monostearate; sorbitan monooleate; othersorbitan esters of long chain carboxylic acids; succinylatedmonoglycerides; stearyl monoglyceryl citrate; stearyl heptanoate; cetylesters of waxes; cetearyl octanoate; C10-C30 cholesterol/lavosterolesters; sucrose long chain carboxylic acid esters; and mixtures thereof.

The alcohols useful as excipient materials for controlled releasematrices can include the hydroxyl forms of the carboxylic acidsexemplified above and also cetearyl alcohol.

In addition, waxes can be useful alone or in combination with thematerials listed above, as excipient materials for the controlledrelease matrix embodiments of the present invention. Non-limitingexamples of these include white wax, paraffin, microcrystalline wax,carnauba wax, and mixtures thereof.

The lipophilic agent can be present in an amount of from 5% to 90% byweight of the controlled release matrix dosage form. For example, incertain embodiments the lipophilic agent is present in an amount of from10% to 85%, and in other embodiments from 30% to 60% by weight of thecontrolled release matrix dosage form.

Non-limiting examples of hydrophilic polymers that can be used incertain embodiments of the controlled release matrix dosage form includehydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC),hydroxyethylcellulose (HEC), carboxymethylcellulose (CMC) or othercellulose ethers, polyoxyethylcne, alginic acid, acrylic acidderivatives such as polyacrylic acid, Carbopol (B. F. Goodrich,Cleveland, Ohio), polymethacrylate polymer such as EUDRAGIT® RL, RS, R,S, NE and E (Rhome Pharma, Darmstadt, Germany), acrylic acid polymer,methacrylic acid polymer, hydroyethyl methacrylic acid (HEMA) polymer,hydroxymethyl methacrylic acid (HMMA) polymer, polyvinyl alcohols.

The hydrophilic polymer can be present in an amount of from 10% to 90%by weight of the controlled release matrix dosage form. For example, incertain embodiments the hydrophilic polymer is present in an amount offrom 20% to 75%, and in other embodiments from 30% to 60% by weight ofthe controlled release matrix dosage form.

In at least one embodiment, the controlled release matrix dosage formcomprises hydroxypropylmethylcellulose (HPMC). HPMC is an anhydroglucosein which some of the hydroxyl groups are substituted with methyl groupsto form methyl ether moieties, and others are substituted withhydroxypropyl groups or with methoxypropyl groups to form hydroxypropylether or methoxypropyl ether moieties. Non-limiting examples ofhydroxypropyl methylcelluloses that are commercially available includeMETHOCEL® E (USP type 2910), METHOCEL® F (USP type 2906), METHOCEL® J(USP type 1828), METHOCEL® K (USP type 2201), and METHOCEL® 310 Series,products of The Dow Chemical Company, Midland, Mich., USA. The averagedegree of methoxyl substitution in these products can range from 1.3 to1.9 (of the three positions on each unit of the cellulose polymer thatare available for substitution) while the average degree ofhydroxypropyl substitution per unit expressed in molar terms can rangefrom 0.13 to 0.82. The dosage form can comprise the different HPMCgrades having different viscosities. The size of a HPMC polymer isexpressed not as molecular weight but instead in terms of its viscosityas a 2% solution by weight in water. Different HPMC grades can becombined to achieve the desired viscosity characteristics. For example,the at least one pharmaceutically acceptable polymer can comprise twoHPMC polymers such as for example METHOCEL® K3 LV (which has a viscosityof 3 cps) and METHOCEL® K100M CR (which has a viscosity of 100,000 cps).In addition, the polymer can comprise two hydroxypropylcellulose formssuch as KLUCEL® LF and KLUCEL® EF. In addition, the at least one polymercan comprise a mixture of a KLUCEL® and a METHOCEL®.

In at least one embodiment the controlled release matrix dosage formcomprises a polyethylene oxide (PEO). PEO is a linear polymer ofunsubstituted ethylene oxide. In certain embodiments poly(ethyleneoxide) polymers having viscosity-average molecular weights of 100,000daltons and higher are used. Non-limiting examples of poly(ethyleneoxide)s that are commercially available include: POLYOX® NF, grade WSRCoagulant, molecular weight 5 million; POLYOX® grade WSR 301, molecularweight 4 million; POLYOX® grade WSR 303, molecular weight 7 million;POLYOX® grade WSR N-60K, molecular weight 2 million; and mixturesthereof. These particular polymers are products of Dow Chemical Company,Midland, Mich., USA. Other examples of polyethylene oxides exist and canlikewise be used. The required molecular weight for the PEO can beobtained by mixing PEO of differing molecular weights that are availablecommercially.

In at least one embodiment of the controlled release matrix dosage form,PEO and HPMC are combined within the same controlled release matrix. Incertain embodiments, the poly(ethylene oxide)s have molecular weightsranging from 2,000,000 to 10,000,000 Da. For example, in at least oneembodiment the polyethylene oxides have molecular weights ranging from4,000,000 to 7,000,000 Da. In certain embodiments the HPMC polymers havea viscosity within the range of 4,000 centipoise to 200,000 centipoise.For example, in at least one embodiment the HPMC polymers have aviscosity of from 50,000 centipoise to 200,000 centipoise, and in otherembodiments from 80,000 centipoise to 120,000 centipoise. The relativeamounts of PEO and HPMC within the controlled release matrix can varywithin the scope of the invention. In at least one embodiment thePEO:HPMC weight ratio is from 1:3 to 3:1. For example, in certainembodiments the PEO:HPMC weight ratio is from 1:2 to 2:1. As for thetotal amount of polymer relative to the entire matrix, this can vary aswell and can depend on the desired drug loading. In at least oneembodiment the total amount of polymer in the matrix can constitute from15% to 90% by weight of the matrix dosage form. For example, in certainembodiments the total amount of polymer in the matrix is from 20% to75%, in other embodiments from 30% to 60%, and in still otherembodiments from 10% to 20% by weight of the matrix dosage form.

In at least one embodiment of the invention the controlled releasematrix dosage form comprises a hydrophobic polymer such asethylcellulose. The viscosity of ethylcellulose can be selected in orderto influence of rate the drug release. In certain embodiments theethylcellulose has a viscosity from 7 to 100 cP (when measured as a 5%solution at 25° C. in an Ubbelohde viscometer, using a 80:20toluene:ethanol solvent.) In certain embodiments the hydrophobic polymercan constitute from 10% to 90% by weight of the matrix dosage form. Forexample, in at least one embodiment the hydrophobic polymer constitutesfrom 20% to 75%, and in other embodiments from 30% to 60% by weight ofthe matrix dosage form.

In at least one embodiment of the invention the controlled releasematrix dosage form comprises at least one binder. In certain embodimentsthe binder is water-insoluble. Examples of binders include hydrogenatedvegetable oil, castor oil, paraffin, higher aliphatic alcohols, higheralphatic acids, long chain fatty acids, fatty acid esters, wax-likematerials such as fatty alcohols, fatty acid esters, fatty acidglycerides, hydrogenated fats, hydrocarbons, normal waxes, stearic acid,stearyl alcohol, hydrophobic and hydrophilic polymers having hydrocarbonbackbones, and mixtures thereof. Non-limiting examples of water-solublepolymer binders include modified starch, gelatin, polyvinylpyrrolidone,cellulose derivatives (such as for example hydroxypropyl methylcellulose(HPMC) and hydroxypropyl cellulose (HPC)), polyvinyl alcohol andmixtures thereof. In at least one embodiment, the binder can be presentin an amount of from 0.1% to 20% by weight of the matrix dosage form.For example, in certain embodiments the binder is present in an amountof from 0.5% to 15%, and in other embodiments from 2% to 10% by weightof the matrix dosage form.

In at least one embodiment of the invention the controlled releasematrix dosage form comprises at least one lubricant. Non-limitingexamples of lubricants include stearic acid, hydrogenated vegetable oils(such as hydrogenated cottonseed oil (STEROTEX®), hydrogenated soybeanoil (STEROTEX® HM) and hydrogenated soybean oil & castor wax (STEROTEX®K)) stearyl alcohol, leucine, polyethylene glycol (MW 1450, suitably4000, and higher), magnesium stearate, glyceryl monostearate, stearicacid, glycerylbehenate, polyethylene glycol, ethylene oxide polymers(for example, available under the registered trademark CARBOWAX® fromUnion Carbide, Inc., Danbury, Conn.), sodium lauryl sulfate, magnesiumlauryl sulfate, sodium oleate, sodium stearyl fumarate, DL-leucine,colloidal silica, and mixtures thereof. The lubricant can be present inan amount of from 0 to 4% by weight of the compressed uncoated matrix.For example, in certain embodiments the lubricant is present in anamount of from 0 to 2.5% by weight of the compressed, uncoated matrix.

In at least one embodiment of the invention the controlled releasematrix dosage form comprises a plasticizer. Non-limiting examples ofplasticizers include dibutyl sebacate, diethyl phthalate, triethylcitrate, tributyl citrate, triacetin, citric acid esters such astriethyl citrate NF XVI, tributyl citrate, dibutyl phthalate,1,2-propylene glycol, polyethylene glycols, propylene glycol, diethylphthalate, castor oil, acetylated monoglycerides, phthalate esters, andmixtures thereof. In at least one embodiment, the plasticizer can bepresent in an amount of from 1% to 70% by weight of the controlledrelease polymer in the matrix dosage form. For example, in certainembodiments the plasticizer is present in an amount of from 5% to 50%,and in other embodiments from 10% to 40% by weight of the controlledrelease polymer in the matrix dosage form.

In at least one embodiment of the invention the controlled releasematrix dosage form comprises at least one diluent, non-limiting examplesof which include dicalcium phosphate, calcium sulfate, lactose orsucrose or other disaccharides, cellulose, cellulose derivatives,kaolin, mannitol, dry starch, glucose or other monosaccharides, dextrinor other polysaccharides, sorbitol, inositol, sucralfate, calciumhydroxyl-apatite, calcium phosphates and fatty acid salts such asmagnesium stearate. In certain embodiments the diluent can be added inan amount so that the combination of the diluent and the activesubstance comprises up to 60%, and in other embodiments up to 50%, byweight of the composition.

In at least one embodiment of the invention the controlled releasematrix dosage form comprises a solubilizer. The solubilizer can act toincrease the instantaneous solubility of the bupropion salt. Thesolubilizer can be selected from hydrophilic surfactants or lipophilicsurfactants or mixtures thereof. The surfactants can be anionic,nonionic, cationic, and zwitterionic surfactants. The hydrophilicnon-ionic surfactants can be selected from the group comprised of, butnot limited to: polyethylene glycol sorbitan fatty acid esters andhydrophilic transesterification products of a polyol with at least onemember of the group from triglycerides, vegetable oils, and hydrogenatedvegetable oils such as glycerol, ethylene glycol, polyethylene glycol,sorbitol, propylene glycol, pentaerythritol, or a saccharide,d-α-tocopheryl polyethylene glycol 1000 succinate. The ionic surfactantscan be selected from the group comprised of, but not limited to:alkylammonium salts; fusidic acid salts; fatty acid derivatives of aminoacids, oligopeptides, and polypeptides; glyceride derivatives of aminoacids, oligopeptides, and polypeptides; lecithins and hydrogenatedlecithins; lysolecithins and hydrogenated lysolecithins; phospholipidsand derivatives thereof; lysophospholipids and derivatives thereof;carnitine fatty acid ester salts; salts of alkylsulfates; fatty acidsalts; sodium docusate; acyl lactylates; mono- and di-acetylatedtartaric acid esters of mono- and di-glycerides; succinylated mono- anddi-glycerides; citric acid esters of mono- and di-glycerides; andmixtures thereof. The lipophilic surfactants can be selected from thegroup comprised of, but not limited to: fatty alcohols; glycerol fattyacid esters; acetylated glycerol fatty acid esters; lower alcohol fattyacids esters; propylene glycol fatty acid esters; sorbitan fatty acidesters; polyethylene glycol sorbitan fatty acid esters; sterols andsterol derivatives; polyoxyethylated sterols and sterol derivatives;polyethylene glycol alkyl ethers; sugar esters; sugar ethers; lacticacid derivatives of mono- and di-glycerides; hydrophobictransesterification products of a polyol with at least one member of thegroup from glycerides, vegetable oils, hydrogenated vegetable oils,fatty acids and sterols; oil-soluble vitamins/vitamin derivatives; PEGsorbitan fatty acid esters, PEG glycerol fatty acid esters,polyglycerized fatty acid, polyoxyethylene-polyoxypropylene blockcopolymers, sorbitan fatty acid esters; and mixtures thereof. In atleast one embodiment the solubilizer can be selected from:PEG-20-glyceryl stearate (CAPMUL® by Abitec), PEG-40 hydrogenated castoroil (CREMOPHOR RH 40® by BASF), PEG 6 corn oil (LABRAFIL® byGattefosse), lauryl macrogol-32 glyceride (GELUCIRE44/14® by Gattefosse)stearoyl macrogol glyceride (GELUCIRE50/13® by Gattefosse),polyglyceryl-10 mono dioleate (CAPROL® PEG860 by Abitec), propyleneglycol oleate (LUTROL® by BASF), Propylene glycol dioctanoate (CAPTEX®by Abitec), Propylene glycol caprylate/caprate (LABRAFAC® byGattefosse), Glyceryl monooleate (PECEOL® by Gattefrosse), Glycerolmonolinoleate (MAISINE® by Gattefrosse), Glycerol monostearate (CAPMUL®by Abitec), PEG-20 sorbitan monolaurate (TWEEN20® by ICI), PEG-4 laurylether (BRIJ30® by ICI), Sucrose distearate (SUCROESTER7® by Gattefosse),Sucrose monopalmitate (SUCROESTER15® by Gattefosse),polyoxyethylene-polyoxypropylene block copolymer (LUTROL® series BASF),polyethylene glycol 660 hydroxystearate, (SOLUTOL® by BASF), Sodiumlauryl sulfate, Sodium dodecyl sulphate, Dioctyl suphosuccinate,L-hydroxypropyl cellulose, hydroxylethylcellulose,hydroxylpropylcellulose, Propylene glycol alginate, sodium taurocholate,sodium glycocholate, sodium deoxycholate, betains, polyethylene glycol(CARBOWAX® by DOW), d-α-tocopheryl polyethylene glycol 1000 succinate,(VITAMIN E TPGS® by Eastman), and mixtures thereof. In at least oneother embodiment the solubilizer can be selected from PEG-40hydrogenated castor oil (CREMOPHOR RH 40® by BASF), lauryl macrogol-32glyceride (GELUCIRE44/14® by Gattefosse) stearoyl macrogol glyceride(GELUCIRE 50/13® by Gattefosse), PEG-20 sorbitan monolaurate (TWEEN 20®by ICI), PEG-4 lauryl ether (BRIJ30® by ICI),polyoxyethylene-polyoxypropylene block copolymer (LUTROL® series BASF),Sodium lauryl sulphate, Sodium dodecyl sulphate, polyethylene glycol(CARBOWAX® by DOW), and mixtures thereof.

In at least one embodiment of the invention the controlled releasematrix dosage form comprises a swelling enhancer. Swelling enhancers aremembers of a special category of excipients that swell rapidly to alarge extent resulting in an increase in the size of the tablet. Atlower concentrations, these excipients can be used assuperdisintegrants; however at concentrations above 5% w/w these agentscan function as swelling enhancers and help increase the size of thematrix dosage form. According to certain embodiments of the matrixdosage forms of the invention, examples of swelling enhancers includebut are not limited to: low-substituted hydroxypropyl cellulose,microcrystalline cellulose, cross-linked sodium or calcium carboxymethylcellulose, cellulose fiber, cross-linked polyvinyl pyrrolidone,cross-linked polyacrylic acid, cross-linked Amberlite resin, alginates,colloidal magnesium-aluminum silicate, corn starch granules, rice starchgranules, potato starch granules, pregelatinised starch, sodiumcarboxymethyl starch and mixtures thereof. In at least one embodiment ofthe matrix dosage forms, the swelling enhancer is cross-linked polyvinylpyrrolidone. The content of the swelling enhancer can be from 5% to 90%by weight of the matrix dosage form. For example, in certain embodimentsthe swelling enhancer is present in an amount of from 10% to 70%, and inother embodiments from 15% to 50% by weight of the matrix dosage form.

In at least one embodiment of the invention the controlled releasematrix dosage form comprises additives for allowing water to penetrateinto the core of the preparation (hereinafter referred to as“hydrophilic base”). In certain embodiments, the amount of waterrequired to dissolve 1 g of the hydrophilic base is not more than 5 ml,and in other embodiments is not more than 4 ml at the temperature of 20°C.±5° C. The higher the solubility of the hydrophilic base in water, themore effective is the base in allowing water into the core of thepreparation. The hydrophilic base includes, inter alia, hydrophilicpolymers such as polyethylene glycol (PEG); (e.g. PEG400, PEG1500,PEG4000, PEG6000 and PEG20000, produced by Nippon Oils and Fats Co.) andpolyvinylpyrrolidone (PVP); (e.g. PVP K30, of BASF), sugar alcohols suchas D-sorbitol, xylitol, or the like, sugars such as sucrose, anhydrousmaltose, D-fructose, dextran (e.g. dextran 40), glucose or the like,surfactants such as polyoxyethylene-hydrogenated castor oil (HCO; e.g.Cremophor RH40 produced by BASF, HCO-40 and HCO-60 produced by NikkoChemicals Co.), polyoxyethylene-polyoxypropylene glycol (e.g. PluronicF68 produced by Asahi Denka Kogyo K.K.), polyoxyethylene-sorbitan highmolecular fatty acid ester (Tween; e.g. Tween 80 produced by KantoKagaku K.K.), or the like; salts such as sodium chloride, magnesiumchloride, or the like; organic acids such as citric acid, tartaric acid,or the like; amino acids such as glycine, .beta.-alanine, lysinehydrochloride, or the like; and amino sugars such as mcglumine. In atleast one embodiment the hydrophilic base is PEG6000, PVP, D-sorbitol,or mixtures thereof.

In another embodiment of the invention the controlled release matrixdosage form comprises at least one disintegrant. Non-limiting examplesof disintegrants for use in the matrix dosage form includecroscarmellose sodium, crospovidone, alginic acid, sodium alginate,methacrylic acid DVB, cross-linked PVP, microcrystalline cellulose,polacrilin potassium, sodium starch glycolate, starch, pregelatinizedstarch and the like. In at least one embodiment the disintegrant isselected from cross-linked polyvinylpyrrolidone (e.g. KOLLIDON® CL),cross-linked sodium carboxymethylcellulose (e.g. Ac-Di-Sol), starch orstarch derivatives such as sodium starch glycolate (e.g. EXPLOTAB®), orcombinations with starch (e.g. PRIMOJEL™), swellable ion-exchangeresins, such as Amberlite IRP 88, formaldehyde-casein (e.g. ESMASPRENG™), and mixtures thereof. In at least one embodiment thedisintegrant is sodium starch glycolate. The disintegrant can be presentin an amount of from 0 to 20% of the total weight of the matrix.

The controlled release matrices of the present invention can furthercontain one or more pharmaceutically acceptable excipients such as,granulating aids or agents, colorants, flavorants, pH adjusters,anti-adherents, glidants and like excipients conventionally used inpharmaceutical compositions.

In at least one embodiment of the invention comprising water swellablepolymers formulated into the matrix, the release kinetics of thebupropion salt from the matrix are dependent upon the relative magnitudeof the rate of polymer swelling at the moving rubbery/glassy front andthe rate of polymer erosion at the swollen polymer/dissolution mediumfront. The release kinetics for the release of the bupropion salt fromthe matrix can be approximated by the following equation:

M _(t) /M _(T) =kt ^(n)

where t is time,M_(t) is the amount of the pharmaceutical agent which has been releasedat time t,M_(T) is the total amount of the pharmaceutical agent contained in thematrix,k is a constant, andn is the release kinetics exponent

This equation is valid so long as n remains nearly constant. When n isequal to one, the release of the pharmaceutical agent from the matrixhas zero-order kinetics. The amount of pharmaceutical agent released isthen directly proportional to the time.

Where the swelling process of the polymer chosen for the excipient isthe primary process controlling the drug release (compared to erosion ofthe swollen polymer), non-zero order release kinetics can result.Generally, these release kinetics dictate a value of n approaching 0.5,leading to square-root Fickian-type release kinetics.

In at least one embodiment of the invention, polymers are selected forinclusion into the formulation to achieve zero order kinetics. Therelease kinetics of the matrix can also be dictated by thepharmaceutical agent itself. A drug which is highly soluble can tend tobe released faster than drugs which have low solubility. Where a drughas high solubility, polymer swelling and erosion must take placerapidly to maintain zero order release kinetics. If the swelling anderosion take place too slowly, the swelling process of the polymer isthe primary process controlling the drug release (since the drug willdiffuse from the swollen polymer before the polymer erodes). In thissituation, non-zero order release kinetics can result. As a result, theadministration of a highly soluble pharmaceutical agent requires arelatively rapidly swelling and eroding excipient. To use such amaterial to produce a matrix which will last for 24 hours can require alarge matrix. To overcome this difficulty, a doughnut-shaped matrix witha hole though the middle can be used with a less rapidly swelling anderoding polymer. With such a matrix, the surface area of the matrixincreases as the matrix erodes. This exposes more polymer, resulting inmore polymer swelling and erosion as the matrix shrinks in size. Thistype of matrix can also be used with very highly soluble pharmaceuticalagents to maintain zero order release kinetics.

In at least one other embodiment of the invention, zero order drugrelease kinetics can be achieved by controlling the surface area of thematrix dosage form that is exposed to erosion. When water is allowed todiffuse into a polymer matrix composition zero order release is obtainedwhen the release rate is governed or controlled by erosion of a constantsurface area per time unit. In order to ensure that the erosion of thepolymer matrix composition is the predominant release mechanism, it ishelpful to provide a polymer matrix composition which has propertiesthat ensures that the diffusion rate of water into the polymer matrixcomposition substantially corresponds to the dissolution rate of thepolymer matrix composition into the aqueous medium. Thus, by adjustingthe nature and amount of constituents in the polymer matrix compositiona zero order release mechanism can be achieved. The compositionsemployed are coated in such a manner that at least one surface isexposed to the aqueous medium and this surface has a substantiallyconstant or controlled surface area during erosion. In the presentcontext controlled surface area relates to a predetermined surface areatypically predicted from the shape of the coat of the unit dosagesystem. It may have a simple uniform cylindrical shape or thecylindrical form can have one or more tapered ends in order to decrease(or increase) the initial release period. Accordingly, these embodimentsprovide a method for controlling the release of a bupropion salt into anaqueous medium by erosion of at least one surface of a pharmaceuticalcomposition comprising

(i) a matrix composition comprising (a) a polymer or a mixture ofpolymers, (b) a bupropion salt and, optionally, (c) one or morepharmaceutically acceptable excipients, and (ii) a coating having atleast one opening exposing at the one surface of said matrix, thecoating comprising: (a) a first cellulose derivative which hasthermoplastic properties and which is substantially insoluble in theaqueous medium in which the composition is to be used, and at least oneof (b) a second cellulose derivative which is soluble or dispersible inwater, (c) optionally a plasticizer, and (d) a filler, the methodcomprising adjusting the concentration and/or the nature of theingredients making up the matrix composition in such a manner that thediffusion rate of the aqueous medium into the matrix compositioncorresponds to 100%±30% such as, for example 100%±25%, 100%±20%,100%±15% or 100%±10%, or 100% of the dissolution rate of the matrixcomposition so as to obtain a zero order release of at least 60% w/wsuch as, for example at least 65% w/w, at least 70% w/w, at least 75%w/w, at least 80% w/w, at least 85% w/w, at least 90% w/w, at least 95%w/w or at least 97% to 98% w/w of the bupropion salt from thepharmaceutical composition when subject to an in vitro dissolution test.

In at least one other embodiment of the invention, zero order drugrelease is approached through the use of: (a) a deposit-core comprisingthe bupropion salt and having defined geometric form, (b) asupport-platform applied to said deposit-core, and is characterized inthat said deposit-core contains, mixed with the bupropion salt, apolymeric material having a high degree of swelling on contact withwater or aqueous liquids, a gellable polymeric material, said polymericmaterials being replaceable by a single polymeric material having bothswelling and gelling properties, and other adjuvants able to provide themixture with suitable characteristics for its compression and for itsintake of water, said support-platform comprising a polymeric materialinsoluble in aqueous liquids and partially coating said deposit-core.

These and further characteristics and advantages of the system accordingto certain embodiments of the matrix dosage form will be more apparentfrom the detailed description of preferred embodiments of the inventiongiven hereinafter by way of non-limiting example. The deposit-core cangenerally be obtained by compressing the mixture containing thebupropion salt to a pressure of between 1000 and 4000 kg/cm², to thusassume a defined geometric form. Polymeric materials having a highdegree of swelling can generally be cross-linked insoluble polymers,whereas gellable polymeric materials are soluble, and can control theintake of water.

The coating platform comprises a polymeric material insoluble in waterand optionally insoluble in biodegradable biological liquids, and ableto maintain its impermeability characteristics at least until thecomplete transfer of the bupropion salt contained in the deposit-core.It is applied to a part of the external deposit-core surface chosen suchas to suitably direct and quantitatively regulate the release of thebupropion salt. In this respect, as the support-platform is impermeableto water, the polymeric material of the deposit-core in certainembodiments can swell only in that portion of the deposit not coatedwith the platform.

The support-platform can be obtained by compressing prechosen polymericmaterials onto the deposit-core, by immersing the deposit-core in asolution of said polymeric materials in normal organic solvents, or byspraying said solutions. Polymeric materials usable for preparing thesupport-platform can be chosen from the class comprising acrylates,celluloses and derivatives such as ethylcellulose, celluloseacetate-propionate, polyethylenes and methacrylates and copolymers ofacrylic acid, polyvinylalcohols etc. This platform can have a thicknessof between 2 mm if applied by compression and 10 microns if applied byspraying or immersion, and comprises from 10% to 90% of the totalsurface of the system.

A factor in controlling the release of the bupropion salt is theintensity and duration of the swelling force developed by the swellablepolymeric materials contained in the deposit-core on contact withaqueous fluids. In this respect, the energy for activating, executingand regulating the release of the bupropion salt can be determined bythe swelling force developed in the deposit-core when this comes intocontact with water or with biological liquids. Said force has anintensity and duration which can vary in relation to the type andquantity of the polymeric materials used in formulating the deposit, andit lies between limits having a maximum value which occurs in the caseof a deposit mainly containing the swellable polymer, and a minimumvalue which occurs in the case of a deposit mainly containing thegellable polymer. Said swellable polymer can be present to the extent ofbetween 5% and 80% by weight, and said gellable polymer to the extent ofbetween 10% and 90% by weight, with respect to the mixture forming thedeposit-core.

A further control factor is the geometry of the support-platform, whichlimits the swelling of the deposit and directs the emission of materialfrom it. Within the scope of these embodiments it is possible toconceive many systems for the controlled release of bupropion salt,which base their operation on the swelling force and differ from eachother by the type of support-platform used.

In at least one other embodiment of the invention designed to achievezero order release of the bupropion salt, the kinetics of drug releasefrom a controlled release matrix is governed by a combination ofdifferent polymers with different swelling characteristics. Morespecifically, the bupropion salt is first granulated with orencapsulated in a less swellable polymer, such as a gum, to form agranule. This granule is disposed in a matrix of a more swellable,erodible polymer. The more swellable erodible polymer has a diffusionrate coefficient which is greater than the diffusion rate coefficient ofthe relatively less swellable polymer. Averaged over the entire periodof drug release, the diffusion rate for the more swellable polymer isgreater than the diffusion rate for the less swellable polymer. It isthis general difference in rates of diffusion between the first andsecond polymers which controls the rate of drug release and allows thesystem to approach zero order drug delivery over the drug releaseperiod. In at least one embodiment, pectin and HPMC are present as themore swellable polymers in ratios of is between 2:7 and 4:5, and gelatinis present as the less swellable polymer.

In at least one other embodiment of the invention there is provided acontrolled release matrix composition comprising bupropion hydrobromideincorporated within a homogeneous matrix including effective amounts ofat least two polymers having opposing wettability characteristics,wherein at least one polymer is selected which demonstrates a strongertendency towards hydrophobicity and the other polymer(s) is selectedwhich demonstrates a stronger tendency towards hydrophilicity. In atleast one embodiment the polymer demonstrating a stronger tendencytowards hydrophobicity is ethylcellulose (EC) whereas the polymerdemonstrating a stronger tendency towards hydrophilicity ishydroxyethylcellulose (HEC) and/or hydroxypropyl methylcellulose (HPMC).The composition and device of the present invention can be provided as amatrix and can be optionally encased in a coating material whichprevents the burst and/or food effect associated with orally ingestedmedicaments and imparts gastrointestinal “stealth” characteristics. Inaccordance with at least one embodiment is a method for preparing adevice for the controlled release of the bupropion salt, the methodcomprising blending bupropion hydrobromide with 5% to 25% by weight ofhydrophilic polymer, and 1% to 25% by weight of hydrophobic polymer,adding suitable pharmaceutical excipients, surface active agents andlubricants, granulating the mixture with solvents such as isopropylalcohol, drying the granular mixture, milling the dried mixture, addingfrom 5% to 70% by weight of ethylcellulose, adding a lubricant andoptionally a glidant and compressing the granules into matrices. Thematrices are optionally encased in a gastrointestinal encasement or apharmaceutically acceptable film coat.

In another embodiment of the present invention, a swellable matrixdosage form is provided in which the bupropion salt is dispersed in apolymeric matrix that is water-swellable rather than merely hydrophilic,that has an erosion rate that is substantially slower than its swellingrate, and that releases the bupropion salt primarily by diffusion. Therate of diffusion of the bupropion salt out of the swellable matrix canbe slowed by increasing the drug particle size, by the choice of polymerused in the matrix, and/or by the choice of molecular weight of thepolymer. The swellable matrix is comprised of a relatively highmolecular weight polymer that swells upon ingestion. In at least oneembodiment the swellable matrix swells upon ingestion to a size that isat least twice its unswelled volume, and that promotes gastric retentionduring the fed mode. Upon swelling, the swellable matrix can alsoconvert over a prolonged period of time from a glassy polymer to apolymer that is rubbery in consistency, or from a crystalline polymer toa rubbery one. The penetrating fluid then causes release of thebupropion salt in a gradual and prolonged manner by the process ofsolution diffusion, i.e., dissolution of the bupropion salt in thepenetrating fluid and diffusion of the dissolved bupropion salt back outof the swellable matrix. The swellable matrix itself is solid prior toadministration and, once administered, remains undissolved in (i.e., isnot eroded by) the gastric fluid for a period of time sufficient topermit the majority of the bupropion salt to be released by the solutiondiffusion process during the fed mode. The rate-limiting factor in therelease of the bupropion salt from the swellable matrix is thereforecontrolled diffusion of the bupropion salt from the swellable matrixrather than erosion, dissolving or chemical decomposition of theswellable matrix.

As such, the swelling of the polymeric matrix can achieve at least thefollowing objectives: (i) renders the matrix sufficiently large to causeretention in the stomach during the fed mode; (ii) localizes the releaseof the drug to the stomach and small intestine so that the drug willhave its full effect without colonic degradation, inactivation, or lossof bioavailability; (iii) retards the rate of diffusion of the drug longenough to provide multi-hour, controlled delivery of the drug into thestomach.

The bupropion salt in the swellable matrix can be present in aneffective amount of from 0.1% to 99% by weight of the matrix. Forexample, in certain embodiments bupropion hydrobromide is present in theswellable matrix in an amount of from 0.1% to 90%, in other embodimentsfrom 5% to 90%, in still other embodiments from 10% to 80%, and in evenstill other embodiments from 25% to 80% by weight of the swellablematrix.

The water-swellable polymer forming the swellable matrix in accordancewith these embodiments of the present invention can be any polymer thatis non-toxic, that swells in a dimensionally unrestricted manner uponimbibition of water, and that provides for a modified release of thebupropion salt. Non-limiting examples of polymers suitable for use inthe swellable matrix include cellulose polymers and their derivatives(such as for example, hydroxyethylcellulose, hydroxypropylcellulose,carboxymethylcellulose, and microcrystalline cellulose, polysaccharidesand their derivatives, polyalkylene oxides, polyethylene glycols,chitosan, poly(vinyl alcohol), xanthan gum, maleic anhydride copolymers,poly(vinyl pyrrolidone), starch and starch-based polymers, poly(2-ethyl-2-oxazoline), poly(ethyleneimine), polyurethane hydrogels, andcrosslinked polyacrylic acids and their derivatives, and mixturesthereof. Further examples include copolymers of the polymers listed inthe preceding sentence, including block copolymers and grafted polymers.Specific examples of copolymers include PLURONIC® and TECTONIC®, whichare polyethylene oxide-polypropylene oxide block copolymers availablefrom BASF Corporation, Chemicals Div., Wyandotte, Mich., USA.

The terms “cellulose” and “cellulosic”, as used within this sectionregarding the swellable matrix embodiments of the present invention, candenote a linear polymer of anhydroglucose. Non-limiting examples ofcellulosic polymers include alkyl-substituted cellulosic polymers thatultimately dissolve in the gastrointestinal (GI) tract in a predictablydelayed manner. In certain embodiments the alkyl-substituted cellulosederivatives are those substituted with alkyl groups of 1 to 3 carbonatoms each. Non-limiting examples include methylcellulose,hydroxymethyl-cellulose, hydroxyethylcellulose, hydroxypropylcellulose,hydroxypropylmethylcellulose, carboxymethylcellulose, and mixturesthereof. In terms of their viscosities, one class of alkyl-substitutedcelluloses includes those whose viscosity is within the range of 100 to110,000 centipoise as a 2% aqueous solution at 20° C. Another classincludes those whose viscosity is within the range of 1,000 to 4,000centipoise as a 1% aqueous solution at 20° C. In certain embodiments thealkyl-substituted celluloses are hydroxyethylcellulose andhydroxypropylmethylcellulose. In at least one embodiment thehydroxyethylcellulose is NATRASOL® 250HX NF (National Formulary),available from Aqualon Company, Wilmington, Del., USA.

Polyalkylene oxides that can be used in certain embodiments of theswellable matrices include those having the properties described abovefor alkyl-substituted cellulose polymers. In at least one embodiment thepolyalkylene oxide is poly(ethylene oxide), which term is used herein todenote a linear polymer of unsubstituted ethylene oxide. In at least oneembodiment the poly(ethylene oxide) polymers have molecular weights of4,000,000 and higher. For example, in certain embodiment thepoly(ethylene oxide) polymers have molecular weights within the range of4,500,000 to 10,000,000, and in other embodiments have molecular weightswithin the range of 5,000,000 to 8,000,000. In certain embodiments thepoly(ethylene oxide)s are those with a weight-average molecular weightwithin the range of 1×105 to 1×107, and in other embodiments within therange of 9×105 to 8×106. Poly(ethylene oxide)s are often characterizedby their viscosity in solution. For example, in certain embodiments thepoly(ethylene oxide)s have a viscosity range of 50 to 2,000,000centipoise for a 2% aqueous solution at 20° C. In at least oneembodiment the poly(ethylene oxide) is one or more of POLYOX® NF, gradeWSR Coagulant, molecular weight 5 million, and grade WSR 303, molecularweight 7 million, both products of Union Carbide Chemicals and PlasticsCompany Inc. of Danbury, Conn., USA. Mixtures thereof are operable.

Polysaccharide gums, both natural and modified (semi-synthetic) can beused in the swellable matrix embodiments of the present invention.Non-limiting examples include dextran, xanthan gum, gellan gum, welangum, rhamsan gum, and mixtures thereof. In at least one embodiment thepolysaccharide gum is xanthan gum.

Crosslinked polyacrylic acids that can be used in the swellable matricesof the present invention include those whose properties are the same asthose described above for alkyl-substituted cellulose and polyalkyleneoxide polymers. In certain embodiments the crosslinked polyacrylic acidsare those with a viscosity ranging from 4,000 to 40,000 centipoise for a1% aqueous solution at 25° C. Non-limiting examples of suitablecrosslinked polyacrylic acids include CARBOPOL® NF grades 971P, 974P and934P (BFGoodrich Co., Specialty Polymers and Chemicals Div., Cleveland,Ohio, USA). Further examples of suitable crosslinked polyacrylic acidsinclude polymers known as WATER LOCK®, which arestarch/acrylates/acrylamide copolymers available from Grain ProcessingCorporation, Muscatine, Iowa, USA.

The hydrophilicity and water swellability of these polymers can causethe drug-containing swellable matrices to swell in size in the gastriccavity due to ingress of water in order to achieve a size that can beretained in the stomach when introduced during the fed mode. Thesequalities also cause the swellable matrices to become slippery, whichprovides resistance to peristalsis and further promotes their retentionin the stomach. The release rate of drug from the swellable matrix isprimarily dependent upon the rate of water imbibition and the rate atwhich the drug dissolves and diffuses from the swollen polymer, which inturn is related to the drug concentration in the swellable matrix. Also,because these polymers dissolve very slowly in gastric fluid, theswellable matrix maintains its physical integrity over at least asubstantial period of time, for example in many cases at least 90% andpreferably over 100% of the dosing period. The particles will thenslowly dissolve or decompose. Complete dissolution or decomposition maynot occur until 24 hours or more after the intended dosing periodceases, although in most cases, complete dissolution or decompositionwill occur within 10 to 24 hours after the dosing period.

The amount of polymer relative to the drug can vary, depending on thedrug release rate desired and on the polymer, its molecular weight, andexcipients that may be present in the formulation. The amount of polymerwill typically be sufficient to retain at least 40% of the drug withinthe swellable matrix one hour after ingestion (or immersion in thegastric fluid). In certain embodiments, the amount of polymer is suchthat at least 50% of the drug remains in the matrix one hour afteringestion; in other embodiments at least 60%, and in still otherembodiments at least 80%, of the drug remains in the swellable matrixone hour after ingestion. In certain embodiments the drug will besubstantially all released from the swellable matrix within ten hours;and in other embodiments within eight hours, after ingestion, and thepolymeric matrix will remain substantially intact until all of the drugis released. In other embodiments the amount of polymer will be suchthat after 2 hours no more than 40% is released; after 4 hours 40-75% isreleased; after 8 hours at least 75% is released and after 16 hours atleast 85% is released. The term “substantially intact” is used herein todenote a polymeric matrix in which the polymer portion substantiallyretains its size and shape without deterioration due to becomingsolubilized in the gastric fluid or due to breakage into fragments orsmall particles.

In other exemplary embodiments the swellable matrix after 2 hours willrelease no more than 40% of the bupropion HBr, after 4 hours from40-75%, after 8 hours at least 75% and after 16 hours at least 85%.

The water-swellable polymers of the swellable matrices can be usedindividually or in combination. Certain combinations will often providea more controlled release of the drug than their components when usedindividually. Examples include cellulose-based polymers combined withgums, such as hydroxyethyl cellulose or hydroxypropyl cellulose combinedwith xanthan gum. Another example is poly(ethylene oxide) combined withxanthan gum.

The benefits of this invention can be achieved over a wide range of drugloadings and polymer levels, with the weight ratio of drug to polymerranging in general from 0.01:99.99 to 80:20. For example, in certainembodiments the drug loadings (expressed in terms of the weight percentof drug relative to total of drug and polymer) are within the range of15% to 80%; in other embodiments within the range of 30% to 80%; and instill other embodiments within the range of 30% to 70%. In at least oneembodiment the drug loading is within the range of 0.01% to 80%, and inat least one other embodiment from 15% to 80%. In at least oneembodiment the weight ratio of bupropion hydrobromide to polymer in theswellable matrix is from 15:85 to 80:20.

The formulations of the swellable matrices of the present invention canassume the form of microparticles, tablets, or microparticles retainedin capsules. In at least one embodiment the formulation comprisesmicroparticles consolidated into a packed mass for ingestion, eventhough the packed mass will separate into individual particles afteringestion. Conventional methods can be used for consolidating themicroparticles in this manner. For example, the microparticles can beplaced in gelatin capsules known in the art as “hard-filled” capsulesand “soft-elastic” capsules. The compositions of these capsules andprocedures for filling them are known among those skilled in drugformulations and manufacture. The encapsulating material should behighly soluble so that the particles are freed and rapidly dispersed inthe stomach after the capsule is ingested.

In certain embodiments of the swellable matrices of the presentinvention, the formulation contains an additional amount of bupropionsalt or other drug applied as a quickly dissolving coating on theoutside of the microparticle or tablet. This coating is referred to as a“loading dose” and it is included for immediate release into therecipient's bloodstream upon ingestion of the formulation without firstundergoing the diffusion process that the remainder of the drug in theformulation must pass before it is released. The “loading dose” can behigh enough to quickly raise the blood concentration of the drug but nothigh enough to produce the transient overdosing that is characteristicof immediate release dosage forms that are not formulated in accordancewith this invention.

In at least one embodiment of the swellable matrices of the presentinvention, the dosage form is a size 0 gelatin capsule containing eithertwo or three pellets of drug-impregnated polymer. For two-pelletcapsules, the pellets are cylindrically shaped, 6.6 or 6.7 mm (or moregenerally, 6.5 to 7 mm) in diameter and 9.5 or 10.25 mm (or moregenerally, 9 to 12 mm) in length. For three-pellet capsules, the pelletsare again cylindrically shaped, 6.6 mm in diameter and 7 mm in length.For a size 00 gelatin capsule with two pellets, the pellets arecylindrical, 7.5 mm in diameter and 11.25 mm in length. For a size 00gelatin capsule with three pellets, the pellets are cylindrical, 7.5 mmin diameter and 7.5 mm in length. In at least one other embodiment, thedosage form is a single, elongated tablet, with dimensions of 18 to 22mm in length, 6.5 to 10 mm in width, and 5 to 7.5 mm in height. In atleast one other embodiment, the dosage form is a single, elongatedtablet, with dimensions of 18 to 22 mm in length, 6.5 to 7.8 mm inwidth, and 6.2 to 7.5 mm in height. In at least one embodiment thedimensions are 20 mm in length, 6.7 mm in width, and 6.4 mm in height.These are merely examples; the shapes and sizes can be variedconsiderably.

The particulate drug/polymer mixture or drug-impregnated swellablepolymer matrix can be prepared by various conventional mixing,comminution and fabrication techniques readily apparent to those skilledin the chemistry of drug formulations. Examples of such techniquesinclude: (1) Direct compression, using appropriate punches and dies,such as those available from Elizabeth Carbide Die Company, Inc.,McKeesport, Pa., USA; the punches and dies are fitted to a suitablerotary tableting press, such as the Elizabeth-Hata single-sided HataAuto Press machine, with either 15, 18 or 22 stations, and availablefrom Elizabeth-Hata International, Inc., North Huntington, Pa., USA; (2)Injection or compression molding using suitable molds fitted to acompression unit, such as those available from Cincinnati Milacron,Plastics Machinery Division, Batavia, Ohio, USA; (3) Granulationfollowed by compression; and (4) Extrusion in the form of a paste, intoa mold or to an extrudate to be cut into lengths.

In regards to the swellable matrices of the present invention, whenmicroparticles are made by direct compression, the addition oflubricants can be helpful and sometimes important to promote powder flowand to prevent capping of the microparticle (breaking off of a portionof the particle) when the pressure is relieved. Non-limiting examples ofsuitable lubricants include magnesium stearate (in a concentration offrom 0.25% to 3% by weight, and in certain embodiments less than 1% byweight, in the powder mix), and hydrogenated vegetable oil (in certainembodiments hydrogenated and refined triglycerides of stearic andpalmitic acids at 1% to 5% by weight, for example in at least oneembodiment at 2% by weight). Additional excipients can be added toenhance powder flowability and reduce adherence.

Certain embodiments of the swellable matrices of the present inventioncan find utility when administered to a subject who is in the digestivestate (also referred to as the postprandial or “fed” mode). Thepostprandial mode is distinguishable from the interdigestive (or“fasting”) mode by their distinct patterns of gastroduodenal motoractivity, which determine the gastric retention or gastric transit timeof the stomach contents.

The controlled release matrices of the present invention can bemanufactured by methods known in the art such as those described in thepatents listed above (e.g. U.S. Pat. No. 5,965,161). An example of amethod of manufacturing controlled release matrices is melt-extrusion ofa mixture containing the bupropion salt, hydrophobic polymer(s),hydrophilic polymer(s), and optionally a binder, plasticizer, and otherexcipient(s) as described above. Other examples of methods ofmanufacturing controlled release matrices include wet granulation, drygranulation (e.g. slugging, roller compaction), direct compression, meltgranulation, and rotary granulation.

Additionally, controlled release particles which can be compressed orplaced in capsules can be produced by combining the bupropion salt and ahydrophobic fusible component and/or a diluent, optionally with arelease modifying agent including a water soluble fusible material or aparticulate soluble or insoluble organic or inorganic material. Examplesof potential hydrophobic fusible components include hydrophobicmaterials such as natural or synthetic waxes or oils (e.g., hydrogenatedvegetable oil, hydrogenated castor oil, microcrystalline wax, Beeswax,carnauba wax and glyceyl monostearate). In at least one embodiment thehydrophobic fusible component has a melting point from 35° C. to 140° C.Examples of release modifying agents include polyethylene glycol andparticulate materials such as dicalcium phosphate and lactose.

In certain embodiments, controlled release matrices can be produced bymechanically working a mixture of bupropion salt, a hydrophobic fusiblecomponent, and optionally a release component including a water solublefusible material or a particulate soluble or insoluble organic orinorganic material under mixing conditions that yield aglomerates,breaking down the agglomerates to produce controlled release seedshaving desired release properties; and optionally adding more carrier ordiluent and repeating the mixing steps until controlled release seedshaving desired release properties are obtained. These particles also canbe size separated (e.g. by sieving and encapsulated in capsules orcompressed into a matrix).

The amount of the hydrophobic fusible material used in the foregoingmethods can range from 10% to 90% by weight. Mixers useful in suchmethods are known and include conventional high-speed mixers withstainless steel interiors. For example, a mixture can be processed untila bed temperature of 40° C. or higher is realized, and the mixtureachieves a cohesive granular texture comprising desired particle sizes.

As noted if the mixture contains agglomerates, they can be broken downusing conventional methods to produce a mixture of powder and particlesof the desired size which, can be size-separated using a sieve, screenor mesh of the appropriate size. This material can be returned to ahigh-speed mixer and further processed as desired until the hydrophobicfusible materials begin to soften/melt, and optionally additionalhydrophobic material can be added and mixing continued until particleshaving a desired size range are obtained. Still further, particlescontaining bupropion salt can be produced by melt processing as known inthe art and combined into capsules or compressed into matrices.

These particles can be combined with one or more excipients such asdiluents, lubricants, binding agents, flow aids, disintegrating agents,surface acting agents, water soluble materials, colorants, and the like.

In addition, the controlled release matrices can optionally be coatedwith one or more functional or non-functional coatings using well-knowncoating methods. Examples of coatings can include the XLcontrol-releasing coat and the EA matrix coating described herein, whichcan further control the release of the bupropion salt and/or other drug.

In at least one embodiment, the controlled release matrices can each becoated with at least one taste-masking coating. The taste-maskingcoating can mask the taste of the bupropion salt in the matrices. In atleast one embodiment the taste-masking coating formulations containpolymeric ingredients. It is contemplated that other excipientsconsistent with the objects of the present invention can also be used inthe taste-masking coating.

In at least one embodiment of the matrix dosage form, the taste-maskingcoating comprises a polymer such as ethylcellulose, which can be used asa dry polymer (such as ETHOCEL®, Dow Corning) solubilised in organicsolvent prior to use, or as an aqueous dispersion. Onecommercially-available aqueous dispersion of ethylcellulose is AQUACOAT®(FMC Corp., Philadelphia, Pa., U.S.A.). AQUACOAT® can be prepared bydissolving the ethylcellulose in a water-immiscible organic solvent andthen emulsifying the same in water in the presence of a surfactant and astabilizer. After homogenization to generate submicron droplets, theorganic solvent is evaporated under vacuum to form a pseudolatex. Theplasticizer is not incorporated in the pseudolatex during themanufacturing phase. Thus, prior to using the same as a coating, theAquacoat is intimately mixed with a suitable plasticizer prior to use.Another aqueous dispersion of ethylcellulose is commercially availableas SURELEASE® (Colorcon, Inc., West Point, Pa., U.S.A.). This productcan be prepared by incorporating plasticizer into the dispersion duringthe manufacturing process. A hot melt of a polymer, plasticizer (e.g.dibutyl sebacate), and stabilizer (e.g. oleic acid) is prepared as ahomogeneous mixture, which is then diluted with an alkaline solution toobtain an aqueous dispersion which can be applied directly ontosubstrates.

In other embodiments of the matrix dosage form, polymethacrylate acrylicpolymers can be employed as taste masking polymers. In at least oneembodiment, the taste masking coating is an acrylic resin lacquer usedin the form of an aqueous dispersion, such as that which is commerciallyavailable from Rohm Pharma under the tradename EUDRAGIT® or from BASFunder the tradename KOLLICOAT®. In further preferred embodiments, theacrylic coating comprises a mixture of two acrylic resin lacquerscommercially available from Rohm Pharma under the tradenames EUDRAGIT®RL and EUDRAGIT® RS, respectively. EUDRAGIT® RL and EUDRAGIT® RS arecopolymers of acrylic and methacrylic esters with a low content ofquaternary ammonium groups, the molar ratio of ammonium groups to theremaining neutral (meth)acrylic esters being 1:20 in EUDRAGIT® RL and1:40 in EUDRAGIT® RS. The mean molecular weight is 150,000. The codedesignations RL (high permeability) and RS (low permeability) refer tothe permeability properties of these agents. EUDRAGIT® RL/RS mixturesare insoluble in water and in digestive fluids. However, coatings formedfrom the same are swellable and permeable in aqueous solutions anddigestive fluids. EUDRAGIT® RL/RS dispersions or solutions of thepresent invention can be mixed together in any desired ratio in order toultimately obtain a taste masking coating having a desirable drugdissolution profile. Desirable controlled release formulations can beobtained, for example, from a retardant coating derived from 100%EUDRAGIT® RL; 50% EUDRAGIT® RL with 50% EUDRAGIT® RS; and 10% EUDRAGIT®RL with 90% EUDRAGIT® RS.

In other embodiments of the matrix dosage form, the taste maskingpolymer can be an acrylic polymer which is cationic in character basedon dimethylaminoethyl methacrylate and neutral methacrylic acid esters(such as EUDRAGIT® E, commercially available from Rohm Pharma). Thehydrophobic acrylic polymer coatings of the present invention canfurther include a neutral copolymer based on poly (meth)acrylates, suchas EUDRAGIT® NE (NE-neutral ester), commercially available from RohmPharma. EUDRAGIT® NE 30D lacquer films are insoluble in water anddigestive fluids, but permeable and swellable.

In other embodiments of the matrix dosage form, the taste maskingpolymer is a dispersion of poly (ethylacrylate, methyl methacrylate) 2:1(KOLLICOAT® EMM 30 D, BASF).

In other embodiments of the matrix dosage form, the taste maskingpolymer can be a polyvinyl acetate stabilized with polyvinylpyrrolidoneand sodium lauryl sulfate such as KOLLICOAT® SR30D (BASF).

Other taste masking polymers used in the matrix dosage forms includehydroxypropylcellulose (HPC); hydroxypropylmethylcellulose (HPMC);hydroxyethylcellulose; gelatin; gelatin/acacia;gelatin/acacia/vinvylmethylether maleic anhydride;gelatin/acacia/ethylenemaleic anhydride; carboxymethyl cellulose;polyvinvylalcohol; nitrocellulose; polyvinylalcohol-polyethylene glycolgraft-copolymers; shellac; wax and mixtures thereof.

The taste-masking coatings can be applied to the matrices from one ormore organic or aqueous solvent solutions or suspensions. In at leastone embodiment of the matrix dosage forms the organic solvents that canbe used to apply the taste-masking coatings include one or more ofacetone, lower alcohols such as ethanol, isopropanol and alcohol/watermixtures, chlorinated hydrocarbons, and the like. Devices used to coatthe matrices of the invention with a taste-masking coating include thoseconventionally used in pharmaceutical processing, such as fluidized bedcoating devices. The control-releasing coatings applied to the matricescan contain ingredients other than the cellulosic polymers. One or morecolorants, flavorants, sweeteners, can also be used in the taste-maskingcoating.

In some embodiments of the matrix dosage forms a pore former can beincluded into the taste masking coat in order to influence the rate ofrelease of bupropion hydrobromide from the matrix. In other embodiments,a pore former is not included in the taste masking coat. The poreformers can be inorganic or organic, and may be particulate in natureand include materials that can be dissolved, extracted or leached fromthe coating in the environment of use. Upon exposure to fluids in theenvironment of use, the pore-formers can for example be dissolved, andchannels and pores are formed that fill with the environmental fluid.

For example, the pore-formers of certain embodiments of the matrixdosage forms can comprise one or more water-soluble hydrophilic polymersin order to modify the release characteristics of the formulation.Examples of suitable hydrophilic polymers used as pore-formers includehydroxypropylmethylcellulose, cellulose ethers and protein-derivedmaterials of these polymers, the cellulose ethers, especiallyhydroxyalkylcelluloses and carboxyalkylcelluloses. Also, syntheticwater-soluble polymers can be used, examples of which includepolyvinylpyrrolidone, cross-linked polyvinyl-pyrrolidone, polyethyleneoxide, water-soluble polydextrose, saccharides and polysaccharides, suchas pullulan, dextran, sucrose, glucose, fructose, mannitol, lactose,mannose, galactose, and sorbitol. In at least one embodiment, thehydrophilic polymer comprises hydroxypropyl-methylcellulose.

Other non-limiting examples of pore-formers include alkali metal saltssuch as lithium carbonate, sodium chloride, sodium bromide, potassiumchloride, potassium sulfate, potassium phosphate, sodium acetate, andsodium citrate. The pore-forming solids can also be polymers which aresoluble in the environment of use, such as Carbowaxes, and Carbopol. Inaddition, the pore-formers embrace diols, polyols, polyhydric alcohols,polyalkylene glycols, polyglycols, and poly(a-w)alkylenediols. Otherpore-formers which can be useful in the formulations of the presentinvention include starch, modified starch, and starch derivatives, gums,including but not limited to xanthan gum, alginic acid, other alginates,benitoniite, veegum, agar, guar, locust bean gum, gum arabic, quincepsyllium, flax seed, okra gum, arabinoglactin, pectin, tragacanth,scleroglucan, dextran, amylose, amylopectin, dextrin, etc., cross-linkedpolyvinylpyrrolidone, ion-exchange resins, such as potassiumpolymethacrylate, carrageenan, kappa-carrageenan, lambda-carrageenan,gum karaya, biosynthetic gum, etc. Other pore-formers include materialsuseful for making microporous lamina in the environment of use, such aspolycarbonates comprised of linear polyesters of carbonic acid in whichcarbonate groups reoccur in the polymer chain, microporous materialssuch as bisphenol, a microporous poly(vinylchloride), micro-porouspolyamides, microporous modacrylic copolymers, microporousstyrene-acrylic and its copolymers, porous polysulfones, halogenatedpoly(vinylidene), polychloroethers, acetal polymers, polyesters preparedby esterification of a dicarboxylic acid or anhydride with an alkylenepolyol, poly(alkylenesulfides), phenolics, polyesters, asymmetric porouspolymers, cross-linked olefin polymers, hydrophilic microporoushiomopolymers, copolymers or interpolymers having a reduced bulkdensity, and other similar materials, poly(urethane), cross-linkedchain-extended poly(urethane), poly(imides), poly(benzimidazoles),collodion, regenerated proteins, semi-solid cross-linkedpoly(vinylpyrrolidone), and mixtures thereof.

In general, the amount of pore-former included in the taste maskingcoatings of certain embodiments of the matrix dosage forms can be from0.1% to 80%, by weight, relative to the combined weight of polymer andpore-former. The percentage of pore former as it relates to the dryweight of the taste-masking polymer, can have an influence on the drugrelease properties of the coated matrix. In at least one embodiment thatuses water soluble pore formers such as hydroxypropylmethylcellulose, ataste masking polymer:pore former dry weight ratio of between 10:1 and1:1 can be present. In certain embodiments the taste maskingpolymer:pore former dry weight ratio is from 8:1 to 1.5:1; and in otherembodiments from 6:1 to 2:1. In at least one embodiment using EUDRAGIT®NE30D as the taste masking polymer and a hydroxypropylmethylcellulose(approx 5 cps viscosity (in a 2% aqueous solution)) such as METHOCEL®E5, Pharmacoat 606G as the water soluble pore former, a taste maskingpolymer:pore former dry weight ratio of 2:1 is present.

Colorants that can be used in the taste-masking coating of certainembodiments of the matrix dosage forms include food, drug and cosmeticcolors (FD&C), drug and cosmetic colors (D&C) or external drug andcosmetic colors (Ext. D&C). These colors are dyes, lakes, and certainnatural and derived colorants. Useful lakes include dyes absorbed onaluminum hydroxide or other suitable carriers.

Flavorants that can be used in the taste-masking coating of certainembodiments of the matrix dosage forms include natural and syntheticflavoring liquids. An illustrative list of such flavorants includesvolatile oils, synthetic flavor oils, flavoring aromatics, oils,liquids, oleoresins and extracts derived from plants, leaves, flowers,fruits, stems and combinations thereof. A non-limiting representativelist of these includes citric oils, such as lemon, orange, grape, limeand grapefruit, and fruit essences, including apple, pear, peach, grape,strawberry, raspberry, cherry, plum, pineapple, apricot, or other fruitflavors. Other useful flavorants include aldehydes and esters, such asbenzaldehyde (cherry, almond); citral, i.e., alpha-citral (lemon, lime);neral, i.e., beta-citral (lemon, lime); decanal (orange, lemon);aldehyde C-8 (citrus fruits); aldehyde C-9 (citrus fruits); aldehydeC-12 (citrus fruits); tolyl aldehyde (cherry, almond);2,6-dimethyloctanal (green fruit); 2-dodenal (citrus mandarin); mixturesthereof and the like.

Sweeteners that can be used in the taste-masking coating of certainembodiments of the matrix dosage forms include glucose (corn syrup),dextrose, invert sugar, fructose, and mixtures thereof (when not used asa carrier); saccharin and its various salts, such as sodium salt;dipeptide sweeteners such as aspartame; dihydrochalcone compounds,glycyrrhizin; Steva Rebaudiana (Stevioside); chloro derivatives orsucrose such as sucralose; and sugar alcohols such as sorbitol,mannitol, xylitol, and the like. Also contemplated are hydrogenatedstarch hydrolysates and the synthetic sweeteners such as3,6-dihydro-6-methyl-1-1-1,2,3-oxathiazin-4-1-2,2-dioxide, particularlythe potassium salt (acesulfame-K), and sodium and calcium salts thereof.The sweeteners can be used alone or in any combination thereof.

The matrix taste masking coat can also include one or morepharmaceutically acceptable excipients such as lubricants, emulsifiers,anti-foaming agents, plasticisers, solvents and the like.

Lubricants can be included to help reduce friction of coated matricesduring manufacturing. The lubricants that can be used in the tastemasking coat of the present invention include but are not limited toadipic acid, magnesium stearate, calcium stearate, zinc stearate,calcium silicate, magnesium silicate, hydrogenated vegetable oils,sodium chloride, sterotex, polyoxyethylene, glyceryl monostearate, talc,polyethylene glycol, sodium benzoate, sodium lauryl sulfate, magnesiumlauryl sulfate, sodium stearyl fumarate, light mineral oil, waxy fattyacid esters such as glyceryl behenate, (i.e. COMPRITOL™), STEAR-O-WET™,MYVATEX™ TL and mixtures thereof. In at least one embodiment, thelubricant is selected from magnesium stearate and talc. Combinations ofthese lubricants are operable. The lubricant can each be present in anamount of from 1% to 100% by weight of the polymer dry weight in thetaste masking coat. For example, in certain embodiments wherein thetaste masking polymer is EUDRAGIT® NE30D or EUDRAGIT® NE40D (RohmAmerica LLC) together with a hydrophilic pore former, the lubricant ispresent in an amount of from 1% to 30% by weight of the polymer dryweight; in other embodiments from 2% to 20%; and in still otherembodiments at 10% by weight of the matrix taste masking coat dryweight. In another embodiment where the taste masking polymer isethylcellulose (ETHOCEL™ PR10, PR45, PR20, PR10 or PR7 polymer, or amixture thereof), the lubricant can be present in an amount of from 10%to 100% by weight of the matrix taste-masking coat dry weight; inanother embodiment from 20% to 80%; and in still another embodiments at50% by weight of the matrix taste masking coat dry weight. In otherembodiments, the taste masking coat does not include a pore former.

Emulsifying agent(s) (also called emulsifiers or emulgents) can beincluded in the matrix taste masking coat to facilitate actualemulsification during manufacture of the coat, and also to ensureemulsion stability during the shelf-life of the product. Emulsifyingagents useful for the matrix taste masking coat composition include, butare not limited to naturally occurring materials and their semisynthetic derivatives, such as the polysaccharides, as well as glycerolesters, cellulose ethers, sorbitan esters (e.g. sorbitan monooleate orSPAN™ 80), and polysorbates (e.g. TWEEN™ 80). Combinations ofemulsifying agents are operable. In at least one embodiment, theemulsifying agent is TWEEN™ 80. The emulsifying agent(s) can be presentin an amount of from 0.01% to 5% by weight of the matrix taste maskingpolymer dry weight. For example, in certain embodiments the emulsifyingagent is present in an amount of from 0.05% to 3%; in other embodimentsfrom 0.08% to 1.5%, and in still other embodiments at 0.1% by weight ofthe matrix taste masking polymer dry weight.

Anti-foaming agent(s) can be included in the matrix taste masking coatto reduce frothing or foaming during manufacture of the coat.Anti-foaming agents useful for the coat composition include, but are notlimited to simethicone, polyglycol, silicon oil, and mixtures thereof.In at least one embodiment the anti-foaming agent is Simethicone C. Theanti-foaming agent can be present in an amount of from 0.1% to 10% ofthe matrix taste masking coat weight. For example, in certainembodiments the anti-foaming agent is present in an amount of from 0.2%to 5%; in other embodiments from 0.3% to 1%, and in still otherembodiments at 0.6% by weight of the matrix taste masking polymer dryweight.

Plasticizer(s) can be included in the matrix taste masking coat toprovide increased flexibility and durability during manufacturing.Plasticisers that can be used in the matrix taste masking coat includeacetylated monoglycerides; acetyltributyl citrate, butyl phthalyl butylglycolate; dibutyl tartrate; diethyl phthalate; dimethyl phthalate;ethyl phthalyl ethyl glycolate; glycerin; propylene glycol; triacetin;tripropioin; diacetin; dibutyl phthalate; acetyl monoglyceride;acetyltriethyl citrate, polyethylene glycols; castor oil; rape seed oil,olive oil, sesame oil, triethyl citrate; polyhydric alcohols, glycerol,glycerin sorbitol, acctate esters, gylcerol triacetate, acetyl triethylcitrate, dibenzyl phthalate, dihexyl phthalate, butyl octyl phthalate,diisononyl phthalate, butyl octyl phthalate, dioctyl azelate, epoxidizedtallate, triisoctyl trimellitate, diethylhexyl phthalate, di-n-octylphthalate, di-i-octyl phthalate, di-i-decyl phthalate, di-n-undecylphthalate, di-n-tridecyl phthalate, tri-2-ethylhexyl trimellitate,di-2-ethylhexyl adipate, di-2-ethylhexyl sebacate, di-2-ethylhexylazelate, dibutyl sebacate, diethyloxalate, diethylmalate,diethylfumerate, dibutylsuccinate, diethylmalonate, dibutylphthalate,dibutylsebacate, glyceroltributyrate, and mixtures thereof. Theplasticizer can be present in an amount of from 1% to 80% of the tastemasking polymer dry weight. For example, in certain embodiments theplasticizer is present in an amount of from 5% to 50%, in otherembodiments from 10% to 40%, and in still other embodiments at 20% ofthe taste masking polymer dry weight.

The taste-masking coating can be present in an amount of from 1% to 90%by weight of the matrix, depending upon the choice of polymer, the ratioof polymer:pore former, and the total surface area of the matrixformulation. Since a certain thickness of taste masking coating has tobe achieved in order to achieve effective taste masking, the amount oftaste masking polymer coating used during manufacture is related to thetotal surface area of the batch of uncoated matrices that requires acoating. For example, the taste masking polymer surface area coveragecan range from 0.5 mg/cm2 to 20 mg/cm2. For example, in certainembodiments the surface area coverage of the taste masking polymer isfrom 0.6 mg/cm2 to 10 mg/cm2, and in other embodiments is from 1 mg/cm2to 5 mg/cm2. In at least one embodiment of the invention, EUDRAGIT® E isemployed as the taste masking polymer at a surface area coverage of 4mg/cm2.

In the absence of an accurate determination of total surface area of amatrix, the amount of taste masking polymer to be applied can beexpressed as a percentage of the uncoated matrix. For example, incertain embodiments the taste-masking coating is present in an amount offrom 5% to 60%; in other embodiments from 10% to 40%; and in still otherembodiments from 15% to 35% by weight of the matrix. In at least oneembodiment the taste-masking coating is present in an amount of 30% byweight of the matrix.

Prophetic examples of matrix tablet formulations are described below. Itshould be understood that these examples are intended to be exemplaryand that the specific constituents, amounts thereof, and formulationmethods may be varied therefrom in order to achieve different releasecharacteristics:

In at least one embodiment, the controlled matrices comprise:

Bupropion HBr 30.0% by weight of the matrix HydroxypropylmethylcelluloseE50 10.0% by weight of the matrix Hydroxypropylmethylcellulose K15M30.0% by weight of the matrix Calcium phosphate dehydrate 9.5% by weightof the matrix ATMUL ™ 84S 20.0% by weight of the matrix (mono/di/triglycerides) Magnesium stearate 0.5% by weight of the matrix

Preparation of the matrix formulation can be as follows: Combine thedrug, a portion of each HPMC, calcium phosphate and Atmul 84S in aplanetary mixer and dry mix for 15 minutes. Add a solution of theremainder of the HPMC in water to the mixer while mixing, until a wetmass is obtained. Pass the wet material through a screen to make theresultant granules of uniform size (to achieve uniform drying) and dryin an oven at 40° C. for 24 hours. Mill the dried granules through aFitzpatrick Mill, knives forward, and collect the material in a mixer.Add the magnesium stearate and mix for 5 minutes. The resultant mixtureis tabletted on a suitable tablet press.

In at least one embodiment, the controlled release matrices comprise adeposit-core and support-platform. Preparation of the deposit-core canbe as follows: Deposit-cores can be prepared using the followingmaterials in the stated quantities:

Bupropion HBr 45.0 g hydroxypropylmethylcellulose 35.0 g (methocel K100M-Colorcon) mannitol 10.0 g ethylcellulose (high viscosity-BDH) 3.75g 3.75 g magnesium stearate 1.0 g 5:1 ethanol-chloroform mixture 75.0 ml

The bupropion HBr is mixed intimately with the mannitol andhydroxypropylmethylcellulose in a suitable mixer. The solution ofethylcellulose in ethanol-chloroform is prepared separately, and is usedfor wetting the previously obtained powder mixture. The resultanthomogeneous mass is forced through an 800 micron screen and then driedto obtain a granulate which is passed through a 420 micron screen. Thehomogeneous granulate obtained is mixed with the magnesium stearate andthen compressed using concave punches of diameter 7 mm (radius ofcurvature 9 mm) using a pressure of 3000 kg/cm2 to obtain cylindricaldeposit-cores with convex bases.

Application of the support-platform can be as follows: Thesupport-platform can be applied by coating one or both the convex basesof the deposit-core with a solution of 15 g low-permeabilityacrylic-methacrylic copolymer (Eudragit RS Rohm Pharma) in methylenechloride of a quantity to make up to 100 ml. Thereafter 0.3 ml of saidsolution is applied to each base to be covered, taking care to protectthe lateral core surface. The system is then dried with tepid air. Thequantity of polymeric material deposited is sufficient to keep thestructure intact during transfer.

In at least one embodiment, the matrix formulation is a PEO based tabletmatrix formulation comprising:

Bupropion HBr 50% PEO WSR Coagulant 15% (polyethylene oxide) MethocelK100M 15% (hydroxypropylmethyl cellulose) Avicel PH101 19%(microcrystalline cellulose) Magnesium Stearate  1%

Preparation of the PEO based tablet matrix formulation can be asfollows: Excipients dry blended in an appropriate mixer and compressedinto tablets using conventional apparatus.

Multiparticulates

Microparticles

In certain embodiments of the present invention, a multiparticulatesystem is provided which contains multiple microparticles eachcontaining an effective amount of a bupropion salt and at least onepharmaceutically acceptable excipient. In at least one embodiment thebupropion salt is bupropion hydrobromide. The multiparticulates can becontained within a capsule, or can be compressed into a matrix ortablet, that upon ingestion dissolves into multiple units (e.g.pellets), wherein the sub-units or pellets possess the desiredcontrolled release properties of the dosage form. The multiparticulatesor the multiple unit dosage forms can be surrounded by one or morecoatings. Examples of such coatings include polymeric controlled releasecoatings, delayed release coatings, enteric coatings, immediate releasecoatings, taste-masking coatings, extended release coatings, andnon-functional coatings.

The bupropion salt in the microparticles can be present in an effectiveamount of from 0.1% to 99% by weight of the microparticles. For example,in certain embodiments bupropion hydrobromide is present in themicroparticles in an amount of from 0.1% to 90%, in other embodimentsfrom 5% to 90%, in still other embodiments from 10% to 80%, and in evenstill other embodiments from 25% to 80% by weight of the microparticle.In certain embodiments wherein the microparticles are manufactured usinga spheronization process, the bupropion hydrobromide can be present inthe microparticles in an amount of from 0.1% to 60%; in other suchembodiments from 5% to 50%; and in still other such embodiments from 10%to 40% by weight of the microparticle. In at least one embodimentwherein the microparticles are manufactured using a spheronizationprocess, the bupropion hydrobromide is present in the microparticle inan amount of 30% by weight of the microparticle.

In addition to the bupropion salt, the microparticles of the presentinvention also include at least one pharmaceutically acceptableexcipient. Excipients can be added to facilitate in the preparation,patient acceptability and functioning of the dosage form as a drugdelivery system. Excipients include spheronization aids, solubilityenhancers, disintegrating agents, diluents, lubricants, binders,fillers, glidants, suspending agents, emulsifying agents, anti-foamingagents, flavouring agents, colouring agents, chemical stabilizers, pHmodifiers, etc. Depending on the intended main function, excipients tobe used in formulating compositions are subcategorized into differentgroups. However, one excipient can affect the properties of acomposition in a series of ways, and many excipients used incompositions can thus be described as being multifunctional.

The microparticles of the present invention can be manufactured usingstandard techniques known to one of skill in the art. Usefulmicroparticles include drug-layered microparticles and drug-containingmicroparticles.

Drug-Containing Microparticles

Microparticles containing drug in the core can be prepared by a numberof different procedures. For example: In a spray drying process, anaqueous solution of core material and hot solution of polymer isatomized into hot air, the water then evaporates, and the dry solid isseparated in the form of pellets, for example by air suspension. Aspray-drying process can produce hollow pellets when the liquidevaporates at a rate that is faster than the diffusion of the dissolvedsubstances back into the droplet interior, or if due to capillary actionthe dissolved substance migrates out with the liquid to the dropletsurface, leaving behind a void. Another example is a spray congealingprocess, where a slurry of drug material that is insoluble in a moltenmass is spray congealed to obtain discrete particles of the insolublematerials coated with the congealed substance. A further example is afluidized bed based granulation/pelletization process, where a dry drugis suspended in a stream of hot air to form a constantly agitatedfluidized bed. An amount of binder or granulating liquid is thenintroduced in a finely dispersed form to cause pelletization.

The drug-containing microparticles of the present invention can also bemade by, for example, a spheronization process. One method ofmanufacturing the drug-containing microparticles is the applicant'sproprietary CEFORM™ (Centrifugally Extruded & FormedMicrospheres/Microparticles) technology, which is the simultaneous useof flash heat and centrifugal force, using proprietary designedequipment, to convert dry powder systems into microparticles of uniformsize and shape. The production of microparticles containing an activedrug using this CEFORM™ technology is described in U.S. Pat. No.5,683,720. This patent deals with the use of LIQUIFLASH® processing tospheronize compositions containing one or more active drugs to formLIQUIFLASH® microparticles.

With the CEFORM™ technology, the processing of the drug-containingmicroparticles of the present invention is carried out in a continuousfashion, whereby a pre-blend of drug and excipients is fed into aspinning “microsphere head”, also termed as a “spheronizing head”. Themicrosphere head, which is a multi-aperture production unit, spins onits axis and is heated by electrical power. The drug and excipient(s)pre-blend is fed into the center of the head with an automated feeder.The material moves, via centrifugal force, to the outer rim where theheaters, located in the rim of the head, heat the material.Microparticles are formed when the molten material exits the head, whichare then cooled by convection as they fall to the bottom of theMicroparticle Chamber. The product is then collected and stored insuitable product containers. Careful selection of the types and levelsof excipient(s) control microparticle properties such as sphericity,surface morphology, and dissolution rate. One advantage of such aprocess is that the microparticles are produced and collected from a dryfeedstock without the use of any solvents.

There are at least two approaches that can be used to producedrug-containing microparticles using the CEFORM process: (i) theencapsulation approach and (ii) the co-melt approach. In theencapsulation approach, the process is conducted below the melting pointof the drug. Therefore, the excipients are designed to melt and entrainthe drug particles on passing through the apertures to formmicroparticles. The resulting microparticles contain the drug, in itsnative state, essentially enveloped by or as an intimate matrix with theresolidified excipients. In the co-melt approach, the process isconducted above the melting point of the drug. In this case, the drugand the excipients melt or become fluid simultaneously upon exposure tothe heat. The molten mixture exits the head and forms microparticles,which cool as they fall to the bottom of the collection bin where theyare collected.

In at least one embodiment the microparticles are manufactured using theencapsulation approach. In the encapsulation approach the excipient(s)which are chosen have a lower melting point than the drug with whichthey will be combined. Therefore the spheronizing process can beperformed at lower temperatures, than the melting point of the drug. Asa result, this can reduce the risk of polymeric interconversion, whichcan occur when using processing temperatures close to the melting point.

In a prophetic example of certain embodiments of the present invention,the manufacturing process for the microparticles can hypothetically beas follows: Spheronization aid is screened through a 425 micron (m)screen. In at least one embodiment, the spheronization aid is distilledglyceryl monostearate (i.e. DMG-03VF). 50% of the spheronization aid isadded to a bowl in a high shear mixer. In at least one embodiment, thebowl is a 6 litre bowl and the high shear mixer is a Diosna P1-6 highspeed mixer granulator. The active drug is then added to the bowl of themixer, and then the remainder of the spheronization aid is added. Thematerial is then blended in the mixer for a time from 1 minute to 30minutes; preferably from 3 minutes to 10 minutes; and more preferably 6minutes. The mixer motor speed is from 50 rpm to 2000 rpm; preferablyfrom 200 rpm to 500 rpm; and more preferably 300 rpm. The chopper motorspeed is from 50 rpm to 2000 rpm; preferably from 200 rpm to 500 rpm;and more preferably 400 rpm. The blended material is then spheronized ina CEFORM™ spheronizing head. The spheronizing head speed is from 5 Hz to60 Hz; preferably from 10 Hz to 30 Hz; and more preferably 15 Hz. In atleast one embodiment the CEFORM™ spheronizing head is a 5 inch head. Thespheronizing head temperature is maintained at a temperature from 70° C.to 130° C.; preferably from 90° C. to 110° C.; and more preferably 100°C. The microparticles obtained from the spinning process are thenscreened through a screen that is from 150 μm to 800 μm.

For microparticles manufactured using a spheronization process such asthe CEFORM™ process, the microparticles include, in addition to thebupropion salt, at least one spheronization aid. Spheronization aids canassist the drug-containing mix to form robust durable sphericalparticles. Some examples of materials useful as spheronization aidsinclude, but are not limited to glyceryl monostearate, glycerylbehenate, glyceryl dibehenate, glyceryl palmitostearate, hydrogenatedoils such as hydrogenated castor oil marketed under the name CUTINA™ HR,fatty acid salts such as magnesium or calcium stearate, polyols such asmannitol, sorbitol, xylitol, stearic acid, palmitic acid, sodium laurylsulfate, polyoxyethylene ethers, esterified polyoxyethylenes such asPEG-32 distearate, PEG-150 distearate, cetostearyl alcohol, waxes (e.g.carnauba wax, white wax, paraffin wax) and wax-like materials. Certainthermo-plastic or thermo-softening polymers can also function asspheronization aids. Some non-limiting examples of such thermo-plasticor thermo-softening polymers include Povidone, cellulose ethers andpolyvinylalcohols. Combinations of spheronization aids can be used. Inat least one embodiment, the spheronization aid is glyceryl monostearate(i.e. DMG-03VF). The spheronization aid can be present in an amount offrom 0.1% to 99% by weight of the microparticle. For example, in certainembodiments the spheronization aid is present in an amount of 5% to 90%;in other embodiments from 10% to 80%; in still other embodiments from20% to 70%; and in even still other embodiments from 30% to 60% byweight of the microparticle. In at least one embodiment thespheronization aid is present in an amount of 50% by weight of themicroparticle. In at least one other embodiment, the microparticlesinclude 50% (w/w) of bupropion hydrobromide and 50% (w/w) of thespheronization aid.

In certain embodiments, each microparticle can also include at least onesolubility enhancer. Solubility enhancers can be surfactants. Certainembodiments of the invention include a solubility enhancer that is ahydrophilic surfactant. Hydrophilic surfactants can be used to provideany of several advantageous characteristics to the compositions,including: increased solubility of the buproprion salt in themicroparticle; improved dissolution of the buproprion salt; improvedsolubilization of the bupropion salt upon dissolution; enhancedabsorption and/or bioavailability of the bupropion salt. The hydrophilicsurfactant can be a single hydrophilic surfactant or a mixture ofhydrophilic surfactants, and can be ionic or non-ionic.

Likewise, various other embodiments of the invention include alipophilic component, which can be a lipophilic surfactant, including amixture of lipophilic surfactants, a triglyceride, or a mixture thereof.The lipophilic surfactant can provide any of the advantageouscharacteristics listed above for hydrophilic surfactants, as well asfurther enhancing the function of the surfactants. These variousembodiments are described in more detail below.

As is well known in the art, the terms “hydrophilic” and “lipophilic”are relative terms. To function as a surfactant, a compound includespolar or charged hydrophilic moieties as well as non-polar hydrophobic(lipophilic) moieties; i.e., a surfactant compound is amphiphilic. Anempirical parameter commonly used to characterize the relativehydrophilicity and lipophilicity of non-ionic amphiphilic compounds isthe hydrophilic-lipophilic balance (the “HLB” value). Surfactants withlower HLB values are more lipophilic, and have greater solubility inoils, whereas surfactants with higher HLB values are more hydrophilic,and have greater solubility in aqueous solutions.

Using HLB values as a rough guide, hydrophilic surfactants can generallybe considered to be those compounds having an HLB value greater than 10,as well as anionic, cationic, or zwitterionic compounds for which theHLB scale is not generally applicable. Similarly, lipophilic surfactantscan be compounds having an HLB value less than 10.

It should be appreciated that the HLB value of a surfactant is merely arough guide generally used to enable formulation of industrial,pharmaceutical and cosmetic emulsions. For many important surfactants,including several polyethoxylated surfactants, it has been reported thatHLB values can differ by as much as 8 HLB units, depending upon theempirical method chosen to determine the HLB value (Schott, J. Pharm.Sciences, 79(1), 87-88 (1990)). Likewise, for certain polypropyleneoxide containing block copolymers (poloxamers, available commercially asPLURONIC® surfactants, BASF Corp.), the HLB values may not accuratelyreflect the true physical chemical nature of the compounds. Finally,commercial surfactant products are generally not pure compounds, but areoften complex mixtures of compounds, and the HLB value reported for aparticular compound may more accurately be characteristic of thecommercial product of which the compound is a major component. Differentcommercial products having the same primary surfactant component can,and typically do, have different HLB values. In addition, a certainamount of lot-to-lot variability is expected even for a singlecommercial surfactant product. Keeping these inherent difficulties inmind, and using HLB values as a guide, one skilled in the art canreadily identify surfactants having suitable hydrophilicity orlipophilicity for use in the present invention, as described herein.

Solubility enhancers can be any surfactant suitable for use inpharmaceutical compositions. Suitable surfactants can be anionic,cationic, zwitterionic or non-ionic. Such surfactants can be groupedinto the following general chemical classes detailed in Tables 81-98herein. The HLB values given in Tables 81-98 below generally representthe HLB value as reported by the manufacturer of the correspondingcommercial product. In cases where more than one commercial product islisted, the HLB value in the Tables is the value as reported for one ofthe commercial products, a rough average of the reported values, or avalue that, in the judgment of the present inventors, is more reliable.

It should be emphasized that the invention is not limited to thesurfactants in Tables 81-98, which show representative, but notexclusive, lists of available surfactants. In addition, refined,distilled or fractionated surfactants, purified fractions thereof, orre-esterified fractions, are also within the scope of the invention,although not specifically listed in the Tables.

Although polyethylene glycol (PEG) itself does not function as asurfactant, a variety of PEG-fatty acid esters have useful surfactantproperties. Examples of polyethoxylated fatty acid monoester surfactantscommercially available are shown in Table 81.

Polyethylene glycol (PEG) fatty acid diesters are also suitable for useas surfactants in the compositions of the present invention.Representative PEG-fatty acid diesters are shown in Table 82.

In general, mixtures of surfactants are also useful in the presentinvention, including mixtures of two or more commercial surfactantproducts. Several PEG-fatty acid esters are marketed commercially asmixtures or mono- and diesters. Representative surfactant mixtures areshown in Table 83.

Suitable PEG glycerol fatty acid esters are shown in Table 84.

A large number of surfactants of different degrees of lipophilicity orhydrophilicity can be prepared by reaction of alcohols or polyalcoholswith a variety of natural and/or hydrogenated oils. In certainembodiments, the oils used are castor oil or hydrogenated castor oil oran edible vegetable oil such as corn oil, olive oil, peanut oil, palmkernel oil, apricot kernel oil, or almond oil. Examples of alcoholsinclude glycerol, propylene glycol, ethylene glycol, polyethyleneglycol, sorbitol, and pentaerythritol. Representative surfactants ofthis class suitable for use in the present invention are shown in Table85.

Polyglycerol esters of fatty acids are also suitable surfactants for thepresent invention. Examples of suitable polyglyceryl esters are shown inTable 86.

Esters of propylene glycol and fatty acids are suitable surfactants foruse in the present invention. Examples of surfactants of this class aregiven in Table 87.

In general, mixtures of surfactants are also suitable for use in thepresent invention. In particular, mixtures of propylene glycol fattyacid esters and glycerol fatty acid esters are suitable and arecommercially available. Examples of these surfactants are shown in Table88.

Another class of surfactants is the class of mono- and diglycerides.These surfactants are generally lipophilic. Examples of thesesurfactants are given in Table 89.

Sterols and derivatives of sterols are suitable surfactants for use inthe present invention. These surfactants can be hydrophilic orlipophilic. Examples of surfactants of this class are shown in Table 90.

A variety of PEG-sorbitan fatty acid esters are available and aresuitable for use as surfactants in the present invention. In general,these surfactants are hydrophilic, although several lipophilicsurfactants of this class can be used. Examples of these surfactants areshown in Table 91.

Ethers of polyethylene glycol and alkyl alcohols are suitablesurfactants for use in the present invention. Examples of thesesurfactants are shown in Table 92.

Esters of sugars are suitable surfactants for use in the presentinvention. Examples of such surfactants are shown in Table 93.

Several hydrophilic PEG-alkyl phenol surfactants are available, and aresuitable for use in the present invention. Examples of these surfactantsare shown in Table 94.

The POE-POP block copolymers are a unique class of polymericsurfactants. The unique structure of the surfactants, with hydrophilicPOE and lipophilic POP moieties in well-defined ratios and positions,provides a wide variety of surfactants suitable for use in the presentinvention. These surfactants are available under various trade names,including SYNPERONIC™ PE series (ICI); PLURONIC® series (BASF),EMKALYX™, LUTROL™ (BASF), SUPRONIC™ MONOLAN™, PLURACARE™, and PLURODAC™.The generic term for these polymers is “poloxamer” (CAS 9003-11-6).These polymers have the formula:

HO(C₂H₄O)_(a)(C₃H₆₀)_(b)(C₂H₄O)_(a)H

where “a” and “b” denote the number of polyoxyethylene andpolyoxypropylene units, respectively. Examples of suitable surfactantsof this class are shown in Table 95.

Sorbitan esters of fatty acids are suitable surfactants for use in thepresent invention. Examples of these surfactants are shown in Table 96.

Esters of lower alcohols (C2 to C4) and fatty acids (C8 to C18) aresuitable surfactants for use in the present invention. Examples of thesesurfactants are shown in Table 97.

Ionic surfactants, including cationic, anionic and zwitterionicsurfactants, are suitable hydrophilic surfactants for use in the presentinvention. In certain embodiments, the surfactant is an anionicsurfactant such as a fatty acid salt, a bile salt, or a combinationthereof. In other embodiments the surfactant is a cationic surfactantsuch as a carnitine. Examples of ionic surfactants include sodiumoleate, sodium lauryl sulfate, sodium lauryl sarcosinate, sodium dioctylsulfosuccinate, sodium cholate, sodium taurocholate; lauroyl carnitine;palmitoyl carnitine; and myristoyl carnitine. Examples of suchsurfactants are shown in Table 98.

Ionizable surfactants, when present in their unionized (neutral,non-salt) form, are lipophilic surfactants suitable for use in thecompositions of the present invention. Particular examples of suchsurfactants include free fatty acids, particularly C6-C22 fatty acids,and bile acids. More specifically, suitable unionized ionizablesurfactants include the free fatty acid and bile acid forms of any ofthe fatty acid salts and bile salts shown in Table 98.

Derivatives of oil-soluble vitamins, such as vitamins A, D, E, K, etc.,are also useful surfactants for the compositions of the presentinvention. An example of such a derivative is tocopheryl PEG-1000succinate (TPGS, available from Eastman).

In certain embodiments, surfactants or mixtures of surfactants thatsolidify at ambient room temperature are used. In other embodiments,surfactants or mixtures of surfactants that solidify at ambient roomtemperature in combination with particular lipophilic components, suchas triglycerides, or with addition of appropriate additives, such asviscosity modifiers, binders, thickeners, and the like, are used.

Examples of non-ionic hydrophilic surfactants include alkylglucosides;alkylmaltosides; alkylthioglucosides; lauryl macrogolglycerides;polyoxyethylene alkyl ethers; polyoxyethylene alkylphenols; polyethyleneglycol fatty acids esters; polyethylene glycol glycerol fatty acidesters; polyoxyethylene sorbitan fatty acid esters;polyoxyethylene-polyoxypropylene block copolymers; polyglycerol fattyacid esters; polyoxyethylene glycerides; polyoxyethylene sterols,derivatives, and analogues thereof; polyoxyethylene vegetable oils;polyoxyethylene hydrogenated vegetable oils; reaction mixtures ofpolyols with fatty acids, glycerides, vegetable oils, hydrogenatedvegetable oils, and sterols; sugar esters, sugar ethers;sucroglycerides; polyethoxylated fat-soluble vitamins or derivatives;and mixtures thereof.

In certain embodiments, the non-ionic hydrophilic surfactant is selectedfrom the group consisting of polyoxyethylene alkylethers; polyethyleneglycol fatty acids esters; polyethylene glycol glycerol fatty acidesters; polyoxyethylene sorbitan fatty acid esters;polyoxyethylene-polyoxypropylene block copolymers; polyglyceryl fattyacid esters; polyoxyethylene glycerides; polyoxyethylene vegetable oils;and polyoxyethylene hydrogenated vegetable oils. The glyceride can be amonoglyceride, diglyceride, triglyceride, or a mixture thereof.

In certain other embodiments, the surfactants used are non-ionichydrophilic surfactants that are reaction mixtures of polyols and fattyacids, glycerides, vegetable oils, hydrogenated vegetable oils orsterols. These reaction mixtures are largely composed of thetransesterification products of the reaction, along with often complexmixtures of other reaction products. The polyol can be glycerol,ethylene glycol, polyethylene glycol, sorbitol, propylene glycol,pentaerythritol, a saccharide, or a mixture thereof.

The hydrophilic surfactant can also be, or include as a component, anionic surfactant. Examples of ionic surfactants include alkyl ammoniumsalts; bile acids and salts, analogues, and derivatives thereof; fusidicacid and derivatives thereof; fatty acid derivatives of amino acids,oligopeptides, and polypeptides; glyceride derivatives of amino acids,oligopeptides, and polypeptides; acyl lactylates; mono-,diacetylatedtartaric acid esters of mono-,diglycerides; succinylated monoglycerides;citric acid esters of mono-,diglycerides; alginate salts; propyleneglycol alginate; lecithins and hydrogenated lecithins; lysolecithin andhydrogenated lysolecithins; lysophospholipids and derivatives thereof;phospholipids and derivatives thereof; salts of alkylsulfates; salts offatty acids; sodium docusate; carnitines; and mixtures thereof.

In certain embodiments the ionic surfactants include bile acids andsalts, analogues, and derivatives thereof; lecithins, lysolecithin,phospholipids, lysophospholipids and derivatives thereof; salts ofalkylsulfates; salts of fatty acids; sodium docusate; acyl lactylates;mono-,diacetylated tartaric acid esters of mono-,diglycerides;succinylated monoglycerides; citric acid esters of mono-diglycerides;carnitines; and mixtures thereof.

Examples of ionic surfactants include lecithin, lysolecithin,phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol,phosphatidic acid, phosphatidylserine, lysophosphatidylcholine,lysophosphatidylethanolamine, lysophosphatidylglycerol, lysophosphatidicacid, lysophosphatidylserine, PEG-phosphatidylethanolamine,PVP-phosphatidylethanolamine, lactylic esters of fatty acids,stearoyl-2-lactylate, stearoyl lactylate, succinylated monoglycerides,mono/diacetylated tartaric acid esters of mono/diglycerides, citric acidesters of mono/diglycerides, cholate, taurocholate, glycocholate,deoxycholate, taurodeoxycholate, chenodeoxycholate, glycodeoxycholate,glycochenodeoxycholate, taurochenodeoxycholate, ursodeoxycholate,tauroursodeoxycholate, glycoursodeoxycholate, cholylsarcosine, N-methyltaurocholate, caproate, caprylate, caprate, laurate, myristate,palmitate, oleate, ricinoleate, linoleate, linolenate, stearate, laurylsulfate, teracecyl sulfate, docusate, lauroyl carnitines, palmitoylcarnitines, myristoyl carnitines, and salts and mixtures thereof.

In certain embodiments, ionic surfactants used include lecithin,lysolecithin, phosphatidylcholine, phosphatidylethanolamine,phosphatidylglycerol, lysophosphatidylcholine,PEG-phosphatidylethanolamine, lactylic esters of fatty acids,stearoyl-2-lactylate, stearoyl lactylate, succinylated monoglycerides,mono/diacetylated tartaric acid esters of mono/diglycerides, citric acidesters of mono/diglycerides, cholate, taurocholate, glycocholate,deoxycholate, taurodeoxycholate, glycodeoxycholate, cholylsarcosine,caproate, caprylate, caprate, laurate, oleate, lauryl sulfate, docusate,and salts and mixtures thereof. In at least one embodiment, the ionicsurfactant is selected from lecithin, lactylic esters of fatty acids,stearoyl-2-lactylate, stearoyl lactylate, succinylated monoglycerides,mono/diacetylated tartaric acid esters of mono/diglycerides, citric acidesters of mono/diglycerides, taurocholate, caprylate, caprate, oleate,lauryl sulfate, docusate, and salts and mixtures thereof.

Examples of lipophilic surfactants include alcohols; polyoxyethylenealkylethers; fatty acids; glycerol fatty acid esters; acetylatedglycerol fatty acid esters; lower alcohol fatty acids esters;polyethylene glycol fatty acids esters; polyethylene glycol glycerolfatty acid esters; polypropylene glycol fatty acid esters;polyoxyethylene glycerides; lactic acid derivatives ofmono/diglycerides; propylene glycol diglycerides; sorbitan fatty acidesters; polyoxyethylene sorbitan fatty acid esters;polyoxyethylene-polyoxypropylene block copolymers; transesterifiedvegetable oils; sterols; sterol derivatives; sugar esters; sugar ethers;sucroglycerides; polyoxyethylene vegetable oils; polyoxyethylenehydrogenated vegetable oils; and mixtures thereof.

As with the hydrophilic surfactants, lipophilic surfactants can bereaction mixtures of polyols and fatty acids, glycerides, vegetableoils, hydrogenated vegetable oils, and sterols.

In certain embodiments, the lipophilic surfactants include one or moreselected from the group consisting of fatty acids; lower alcohol fattyacid esters; polyethylene glycol glycerol fatty acid esters;polypropylene glycol fatty acid esters; polyoxyethylene glycerides;glycerol fatty acid esters; acetylated glycerol fatty acid esters;lactic acid derivatives of mono/diglycerides; sorbitan fatty acidesters; polyoxyethylene sorbitan fatty acid esters;polyoxyethylene-polyoxypropylene block copolymers; polyoxyethylenevegetable oils; polyoxyethylene hydrogenated vegetable oils; andreaction mixtures of polyols and fatty acids, glycerides, vegetableoils, hydrogenated vegetable oils, sterols, and mixtures thereof.

In certain other embodiments, the lipophilic surfactants include one ormore selected from the group consisting of lower alcohol fatty acidsesters; polypropylene glycol fatty acid esters; propylene glycol fattyacid esters; glycerol fatty acid esters; acetylated glycerol fatty acidesters; lactic acid derivatives of mono/diglycerides; sorbitan fattyacid esters; polyoxyethylene vegetable oils; and mixtures thereof. Amongthe glycerol fatty acid esters, the esters can be mono- or diglycerides,or mixtures of mono- and diglycerides, where the fatty acid moiety is aC6 to C22 fatty acid.

Other embodiments include lipophilic surfactants which are the reactionmixture of polyols and fatty acids, glycerides, vegetable oils,hydrogenated vegetable oils, and sterols. Examples of polyols arepolyethylene glycol, sorbitol, propylene glycol, pentaerythritol, andmixtures thereof.

Combinations of solubility enhancers (i.e. surfactants) can be used.Examples of macrogol fatty acid esters useful as solubility enhancersinclude GELUCIRE 50/13® and GELUCIRE 44/14®. In at least one embodimentthe solubility enhancer is GELUCIRE 50/13®. The solubility enhancer canbe present in an amount of from 0.1% to 70% by weight of themicroparticle. For example, in certain embodiments, the solubilityenhancer is present in an amount of from 1% to 50%; in other embodimentsfrom 10% to 30%; in still other embodiments from 15% to 25% by weight ofthe microparticle. In at least one embodiment the solubility enhancer ispresent in an amount of 20% by weight of the microparticle.

It is contemplated that in some embodiments, one or more otherpharmaceutically acceptable excipients consistent with the objects ofthe present invention can be used in the microparticles, such as alubricant, a binder, a pH modifier, a filler and/or a glidant.

The process for manufacturing the drug-containing microparticles of thepresent invention by spheronization are not limited to the CEFORM™technology, and any other technology resulting in the formation of themicroparticles consistent with the objects of the present invention canalso be used. For example, microparticles of the invention can also bemanufactured by by extrusion/spheronization, granulation orpelletization.

Extrusion/spheronization is a multi-step process used to make uniformlysized spherical particles. The technique offers the ability toincorporate high levels of active ingredients without producingexcessively large particles. The main steps in the process are:

(i) Dry-mixing of ingredients to achieve a homogenous powder dispersion;

(ii) Wet massing using for example a high-shear wet granulator to formrod shaped particles of uniform diameter

(iii) Extrusion to form rod-shaped particles of uniform diameter;

(iv) Spheronization to round off the rods into spherical particles;

Screening to achieve the desired narrow particle size distribution.

The mixing vessel used for dry-mixing can be of any size and shapecompatible with the size of the formulation to be produced. For example,commercially available mixing devices such as planetary mixers, highshear mixers, or twin cone blenders can be used. If relatively smallquantities of formulation are to be prepared, a simple mortar and pestlecan be sufficient to mix the ingredients. The type of mixing vesselwould be apparent to one skilled in the pharmaceutical art. Themoistened mass formed by wet-massing in conventional granulationequipment is extruded through a perforated mesh in order to producecylindrical filaments. The port of the meshes can determine the diameterof the filaments. A port ranging from 0.2 mm to 3 mm can be used in thisprocess. In at least one embodiment utilizing this process, the portranges from 0.4 mm to 2 mm. The extrusion can be carried out usingscrew, double screw, “sieve and basket” kind, “roll extruder”, “ramextruder” extruders or any other pharmaceutically acceptable means toproduce cylindrical filaments. In certain embodiments utilizing thisextrusion/spheronization process, a double screw coaxial extruder isused. The spheronization device comprises a hollow cylinder with ahorizontal rotating plate. The filaments are broken in short segmentswhich are transformed in spherical or quasi-spherical particles on theupper surface of the rotating plate at a velocity ranging from 200 rpmto 2,000 rpm. The particles can be dried in any pharmaceuticallyacceptable way, such as for example by air drying in a static condition.The particles are used as they are or they are coated to obtain granulesto use in tablets, capsules, packets or other pharmaceuticalformulations.

A prophetic example of an extrusion/spheronization formulationcomprising bupropion hydrobromide can be as follows: In this example,the bupropion hydrobromide can be present in an amount of from 1% to 80%w/w. In certain embodiments within this example, the bupropionhydrobromide is present in an amount of from 1% to 50% w/w; in otherembodiments from 10% to 30%; and in still other embodiments 10% w/w. Inthis example, the filler can be present in an amount of from 0% to 80%w/w. In certain embodiments of this example, the filler is present in anamount of from 10% to 60%; and in other embodiments at 40% w/w. In thisexample, the microcrystalline cellulose can be present in an amount offrom 10% to 90% w/w. In certain embodiments of this example, themicrocrystalline cellulose is present in an amount of from 10% to 70%;and in other embodiments from 20% to 50% w/w. In this example, thebinder can be present in an amount of from 0% to 10% w/w. In certainembodiments of this example, the binder is present in an amount of from1% to 8%; and in other embodiments from 2% to 4% w/w. In this example,water can be present in an amount of from 10% to 80% w/w. In certainembodiments of this example, water is present in an amount of from 15%to 70%; and in other embodiments from 20% to 50% w/w. Suitable fillersin this example include but are not limited to calcium phosphatedibasic, tricalcium phosphate, calcium carbonate, starch (such as corn,maize, potato and rice starches), modified starches (such ascarboxymethyl starch, etc.), microcrystalline cellulose, sucrose,dextrose, maltodextrins, lactose, and fructose. Suitable lubricants inthis example include but are not limited to metal stearates (such ascalcium, magnesium on zinc stearates), stearic acid, hydrogenatedvegetable oils, talc, starch, light mineral oil, sodium benzoate, sodiumchloride, sodium lauryl sulfate, magnesium lauryl sulfate, sodiumstearyl fumarate, glyceryl behenate and polyethylene glycol (such asCARBOWAX™ 4000 and 6000). Suitable antiadherents in this example includebut are not limited to colloidal silicon dioxide. Suitable binders inthis example include but are not limited to ethyl cellulose, apolymethacrylate polymer, polyvinylalcohol, polyvinyl pyrrolidone,polyvinylpyrrolidone-vinylacetate copolymer (e.g. Kollidon VA64)hydroxyethylcellulose, low molecular weight hydroxypropylmethylcellulose(e.g. viscosity of 1-50 cps at 20° C.; 2-12 cps at 20° C.; or 4-6 cps at20° C.), hydroxypropylcellulose polymethacrylates, and mixtures thereof.

The drug-containing microparticles formed by extrusion/spheronization inthis prophetic example can be produced using cross-linked amphiphilicpolymers by the following steps: (a) the mixing of one or morecross-linked amphiphilic polymers with bupropion hydrobromide andoptionally other pharmaceutical excipients in order to obtain a uniformmixture in the form of dry powder to which a suitable amount of liquidis added to obtain a pasty consistency; (b) the extrusion of the mixtureobtained from step (a) through a perforated mesh in order to obtaincylindrical filaments having desired length and diameter; (c) thespheronization of the filaments in order to obtain a product in the formof spherical multiparticulates; (d) the drying of the product; and (e)the optional depositing of a drug on the surface of the microparticles.“Cross-linked amphiphilic polymer” refers in this example to polymersshowing characteristics of swellability in the whole pH range of aqueoussolutions and also in solvents or solvent mixtures having differentpolarity characteristics. The polymers can be cross-linked eitherphysically through the interpenetration of the macromolecular meshes, orchemically, thus showing points of link among the macromolecular chains.Non-limiting examples of such polymers include cross-linked polyvinylpyrrolidone, sodium carboxymethylcellulose, sodium glycolate starch anddextrans. Optional excipients include dispersing, emulsifying, wettingagents and colouring agents. The expression “uniform mixture” in thisexample means that the components of the mixture are uniformly dispersedin the formulation by a mixing process which assures the uniformdistribution of each component. A reasonable mixing time can range from1 to 60 minutes using one of the mixing equipments conventionally usedfor the dry mixing of the powders (e.g. “V”, fixed body, rotating body,sigma mixers). The term “liquid” in this example means any liquidsubstance or mix (solution or emulsion) of liquids of normalpharmaceutical use able to moisten the powder mix, as for example water,aqueous solutions having different pH, organic solvents of normalpharmaceutical use (e.g. alcohols, chlorinated solvents), and oils.Among the oils and surfactants which can be used in this example are:natural oils, either saturated or unsaturated (olive, peanut, soybean,corn, coconut, palm, sesame and similar oils); semisynthetic andsynthetic mono-, di- and triglycerides containing saturated and/orunsaturated fatty acids and their polyhydroxyethylated derivatives(caprico-caprilic triglycerides [MYGLIOL™, CAPTEX™, LABRAFAC™, Lipo],saturated or unsaturated polyhydroxylated triglycerides of various kind[LABRAFIL™, LABRAFAC™ Hydro, GELUCIRE™]); liquid waxes (isopropylmyristate, isopropyl-caprinate, -caprylate, -laurate, -palmitate,-stearate); fatty acids esters (ethyl oleate, oleyl oleate); siliconeoils; polyethylene glycols (PEG 200, PEG 400, PEG 600, PEG 1000, and soon); polyglycolic glycerides (for example LABRASOL™); polyglycols(propylene glycol, tetraglycol, and ethoxydiglycol (TRANSCUTOL™),sorbitan-esters of fatty acids (for example SPAN®, ARLACEL®, BRIJ®),polyoxyethylenesorbitan esters of fatty acids (for example TWEEN®,CAPMUL®, LIPOSORB®), polypropylene oxide-polyethylene oxide (Poloxamer)copolymers, polyethylene glycol esters (PEG)-glycerol (LABRASOL®,LABRAFIL®), PEG esters and long chain aliphatic acids or alcohols (forexample CREMOPHOR®), polyglycerid esters (PLUROL®), saccharide and fattyacid esters (sucro-esters). Moreover, anionic surfactants (for examplesodium lauryl sulfate, sodium stearate, sodium oleate) or cationicsurfactants (for example tricetol), can be used as well as lecithins,phospholipids and their semi-synthetic or synthetic derivatives. Alsobupropion hydrobromide and/or excipients can be dissolved, dispersedand/or emulsified in such liquids.

In a particular embodiment formed by an extrusion/spheronization processfrom the prophetic example described above, the moistening liquidcomprises an oil/surfactant system wherein the bupropion hydrobromideoptionally emulsified with an aqueous phase is dissolved or dispersed.The amount of liquid with respect to the solid used in the preparationof the mixture can range from 1% to 80% by weight. As a propheticexample of this embodiment, a mixture of bupropion hydrobromide andKOLLIDON™ CL in a ratio equal to ⅓ by weight is co-milled obtaining themixture in the form of powder having the 100% of granulometry lower than50 microns. The mixture is moistened using a liquid demineralized watercontaining KOLLIDON™ 25 (polyvinyl pyrrolidone, BASF) in a solution 3%w/w. The extrusion is carried out forcing the moistened mass through athreader having diameter of the holes equal to 1 mm. The operativeparameters in this prophetic example can be as follows: powder flowrate: 4.5 kg/h; liquid flow rate: 4.1 kg/h; torsional stress: 27%; headtemperature: 46° C.; and screw rotation velocity: 140 rpm. The extrusionfilaments are then processed in a spheronizator adjusted at a velocityequal to 1,000 rpm for 2 minutes. The obtained microparticles are thendried in a fluid bed for 2 hours to a maximum temperature equal to 59°C. At the end of the drying the product is discharged and ismechanically screened separating the fraction ranging from 0.7 mm to 1.2mm.

Another prophetic example of a drug-containing microparticle embodimentof the invention formed by an extrusion/spheronization process, uses acharged resin, the steps of which can comprise: (a) adding the chargedresin, bupropion hydrobromide and other excipients, to a mixing vessel;(b) mixing the ingredients to obtain a uniform mixture; (c) adding agranulating solution—a liquid capable of wetting the dry mixture.Liquids resulting in conversion of the dry powder mixture into a wetgranulation that supports subsequent extrusion and spheronization(marumerization) are included. Typically, water or aqueous solutions areemployed. Alcohols, typically ethanol or isopropanol, can be includedwith the granulating water to enhance the workability of thegranulation. In another embodiment of this invention, one or more of thecomponents of the formulation is first dissolved in water and thissolution is used to produce the wet granulation. An active ingredient oran excipient which is present at very low concentration can initially bedissolved or suspended in the granulating solvent to assure more uniformdistribution throughout the formulation. (d) granulating the mixtureuntil a uniform granulation results; (e) extruding the wet granulationthrough a screen to produce strands of granulation; (f) spheronizing thestrands of granulation to produce spherical multiparticulates; and (g)collecting and drying the spherical multiparticulates. By “chargedresin” is meant in this example to mean a polymer with ionizablefunctional groups that becomes useful in the embodiment of thisinvention. This broadly encompasses any polymer that upon ionization, iscapable of producing cationic or anionic polymeric chains and whichsupport spheronization. Typically from 10% to 70% by weight of thespherical multiparticulate is charged resin. Non limiting examples ofthese charged resins include sodium polystyrene sulfonate which is soldunder the trade name AMBERLITE IRP-69™ by Rohm and Haas, Co.,Philadelphia, Pa.; the chloride salt of cholestyramine resin USP, soldas AMBERLITE IRP-276™ by Rohm and Haas, Co., Philadelphia, Pa.; the acidform of methacrylic acid-divinyl benzene, sold as AMBERLITE IRP-64™ byRohm and Haas Co., Philadelphia, Pa.; carboxypolymethylenes sold underthe trade names CARBOPOL™ 974P and CARBOPOL™ 934P by B. F. Goodrich,Inc., Brecksville, Ohio, and sodium polyacrylate, sold under the tradename AQUAKEEP™ J-550 by Seitetsu Kagaku, Japan. In order for the resinto maintain the desired degree of ionization, agents which produce anacidic or basic environment during granulation and spheronization can beincluded within the formulation. Among the groups of compounds that canexert this effect are acids, bases, and the salts of acids and basessuch as adipic acid, citric acid, fumaric acid, tartaric acid, succinicacid, sodium carbonate, sodium bicarbonate, sodium citratc, sodiumacetate, sodium phosphates, potassium phosphates, ammonium phosphate,magnesium oxide, magnesium hydroxide, sodium tartrate, and tromethamine.Certain compounds can be added to the granulation to provide the properdegree of hydration of the charged resin, medicament and excipients.These hydrating agents include sugars such as lactose, sucrose,mannitol, sorbitol, pentaerythritol, glucose and dextrose. Polymers suchas polyethylene glycol as well as surfactants and other organic andinorganic salts can also be used to modulate polymer hydration.

In another prophetic example, multiparticulates containing bupropionhydrobromide can be obtained as follows:

Component Percent w/w Bupropion HBr 8.7 Disodium Phosphate 7.0Monosodium phosphate 1.7 Sodium dodecyl sulfate 21.7 Sodium Chloride17.4 Povidone 29-32K 8.7 AMBERLITE IRP-69 34.8 Butylated Hydroxyanisol0.0002

In this prophetic example, approximately 5.75 kg of the aboveformulation is mixed in a planetary mixer for 15 minutes. The butylatedhydroxyanisol is dissolved in 60 cc of ethanol and water is added tobring the final solution to a volume of 133 cc. This solution is addedto the planetary mixer over a two (2) minute period. The mixer is thengranulated with seven aliquots of 250 cc of water added over a fifteenminute period. The granulation thus formed is extruded through a 1.0 mmscreen and aliquots spheronized by marumerization at approximately 1200rpm for approximately 10 minutes each. The spherical multiparticulatesformed are then dried at 50° C. for 24 hours.

Another embodiment of this invention involves the production of drugcontaining microparticles in the form of ‘pearls’. Pearls can bemanufactured by mixing bupropion hydrobromide with one or morepharmaceutical excipients in molten form; the melt is forced to passthrough a nozzle which is subjected to a vibration; the pearls formedare allowed to fall in a tower countercurrentwise to a gas; and thesolid pearls are collected in the bottom of the tower. In this example,the quantity of bupropion hydrobroimde can vary from 5% to 95% byweight; and in certain embodiments from 40% to 60% by weight. Theadditives which enable the crystallization of the supercooled product tobe induced in this example can be chosen from the following: fattyalcohols such as: cetyl alcohol, stearyl alcohol, fatty acids such as:stearic acid, palmitic acid, glycerol esters such as: glycerolpalmitostearate, the glycerol stearate marketed under the markPRECIROL™, the glycerol behenate marketed under the mark COMPRITOL™,hydrogenated oils such as: hydrogenated castor oil marketed under themark CUTINA™ HR, fatty acid salts such as: magnesium or calciumstearate, polyols such as: mannitol, sorbitol, xylitol, waxes such as:white wax, carnauba wax, paraffin wax, polyoxyethylene glycols of highmolecular weight, and esterified polyoxyethylenes such as: PEG-32distearate, and PEG-150 distearate. To these crystallization additivesit can be desirable in this example to add polymers which are soluble ordispersible in the melt, and which provide a controlled and adjustabledissolution of the pearls when they are used, examples of which include:cellulose derivatives (hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, ethyl cellulose, carboxymethylcellulose), acrylic resins (marketed under the mark EUDRAGIT®),polyvinyl acetates (marketed under the mark RHODOPAS®), polyalkylene(ethylene propylene), polylactic, maleic anhydride and silicone resins.In addition, inorganic additives can be added to accelerate thesolidification of the active substances, examples of which include:silicas, inorganic oxides such as titanium or iron oxide, phosphates,carbonates, clays, and talc. In addition, a surface-active agent can beadded to improve the dispersion of the active substance in thecrystallization additive, examples of which include: sorbitol esters,the polyoxyethylene polysorbates marketed under the mark TWEEN®, andglycols such as glycerine or propylene glycol. The process for thepreparation of pearls comprise preparing a melt of the bupropionhydrobromide with one or more excipients. This melt can be prepared byseparately melting the various constituents and then mixing them or bymelting the mixture of the constituents, possible insoluble compoundsbeing added at the end of the melting so as to obtain a homogeneousmass. The nature of the constituents of the melt is chosen by the personskilled in the art, which is considered as a function of thecompatibility of the constituents, the viscosity of the mixture ofconstituents, the nozzle diameter, the hydrophilicity of the activesubstance, the surface tension of the active substance, the particlesize of the insoluble additives, the flow rate of the nozzle, thetemperature of the tower, its height and, above all, the size of thedesired pearls, the proportion of bupropion hydrobromide to be includedtherein and the desired release time of the active substance.

Alternative procedures other than extrusion or spheronization formanufacturing drug-containing microparticles can include wetgranulation, solvent granulation and melt granulation. All of thesetechniques involve the addition of an inactive binder to aggregatesmaller particles into larger granules. For example, wet granulation andsolvent granulation involve the addition of a liquid binder whichaggregates the active materials and excipients into granules. Aftergranulation, the liquid can be removed by a separate drying step. Meltgranulation is similar to wet granulation, but uses a low melting pointsolid material as a binder. The solid binder in melt granulation ismelted and acts as a liquid binder thereby aggregating the powderedactive material and excipients into granules. The binder thereby, can beincorporated into the granules when the granules cool.

Certain embodiments of the present invention include microparticlesmanufactured by a process for producing granules by rotomelt granulationthat comprises mixing bupropion hydrobromide and a powdered excipientmaterial that has a higher melting point than bupropion hydrobromide ina zone wherein both powdered materials are maintained in a fluidizedstate by a rising stream of gas in an apparatus having a rapidlyrotating horizontal-disk located within a vertical vessel having abottom surface; wherein said rapidly rotating disk is located on thebottom surface of the vertical vessel wherein said gas is at atemperature sufficient to cause the bupropion hydrobromide to at leastpartially melt thereby causing said powdered materials to aggregate andform granules. Other embodiments of the present invention includemicroparticles manufactured by a process for producing granules byrotomelt granulation comprising mixing powdered binder material andbupropion hydrobromide wherein the bupropion hydrobromide has a highermelting point than the powdered binder material in a zone wherein bothpowdered materials are maintained in a fluidized state by a risingstream of gas in an apparatus having a rapidly rotating horizontal-disklocated within a vertical vessel having a bottom surface; and whereinsaid rapidly rotating disk is located on the bottom surface of thevertical vessel wherein said gas is at a temperature sufficient to causethe powdered binder material to at least partially melt thereby causingsaid powdered materials to aggregate and form granules.

In rotomelt granulation, one of the feed powders must have a lowermelting point than the other powder in order to serve as a binder. Thefeed powders are introduced into a vertical vessel with rotatablehorizontal-disk located in the bottom of the vessel. The powder ismaintained in fluidized state by at least one stream of filtered airbeing circulated from the bottom of the vertical vessel through one ormore inlets. The rotatable horizontal disk is then rotated while the airsupplied to fluidize the powder is maintained at a temperaturesufficient to soften or melt the lower melting point powder. Thetemperature to which the binder must be heated to soften can beempirically determined by observing the formation of granules at varioustemperatures for various binders. It is presently believed thattemperatures from 3° C. to 5° C. below the melting point or meltingrange provides sufficient softening to result in granule formation. Thelower melting point powder then acts as a binding agent to promote theaggregation of powder particles into granules. Suitable powders for usein rotomelt granulation have a diameter size in the range of from 5microns to 150 microns; and in certain embodiments have a diameter sizein the range of 35 microns to 80 microns. The temperature which thecomponents will be exposed to depends on the binder employed toaggregate the powders. Generally, the melting point of the binder isabove 30° C.; and in certain embodiments is below 100° C.

The powders used in these microparticles manufactured by rotomeltgranulation can be formed into granules by at least two alternativegranulation mechanisms. The first mechanism for granule formationutilizes a larger particulate binder and a smaller particulate powder.The temperature during the rotomelt granulation is then elevated only tothe point where the external surface of the binder particles becometacky. As the second powdered material of a smaller size is contactedwith the tacky surface it forms a microlayer on the surface of thebinder particle. This granulation mechanism results in granules whichhave size distribution similar to the original binder particlesemployed. Alternatively, the rotomelt granulation can be conducted at atemperature at which the binder acts as a cement bridging the gapsbetween the unmelted particles (this is referred to as agglomeration).This mechanism results in the formation of granules where the componentsare intermingled. For each binder used the mechanism can be controlledprimarily by the temperature at which the rotomelt granulation isperformed. Those skilled in the art will appreciate that the granulesformed can be observed by electron microscopy to determine the type ofgranulation process occurring. If one particular type of granule isdesired, the process conditions or starting materials can be varied toproduce the desired granules.

In at least one embodiment of the present invention, bupropionhydrobromide is melted to act as a binding agent in the rotomeltgranulation process. Examples of suitable excipients include thoseselected from the following: fillers, lubricants, glidants andantiadherents. Suitable fillers include but are not limited to calciumphosphate dibasic, tricalcium phosphate, calcium carbonate, starch (suchas corn, maize, potato and rice starches), modified starches (such ascarboxymethyl starch, etc.), microcrystalline cellulose, sucrose,dextrose, maltodextrins, lactose, and fructose. The amount of binderadded to aggregate the particles into granules can be in the range offrom 10% w/w to 80% w/w; and in certain embodiments is in the range offrom 30% w/w to 70% w/w of the powdered materials in the rotomeltgranulation. The remaining weight percentage to provide a total of 100%w/w can be one or more suitable powdered pharmaceutical actives.Optionally the rotomelt granulation can also contain from 0% to 60% w/wof one or more powdered excipients wherein the total weight of all thepowdered materials equals 100% w/w. The binder used in these embodimentof the invention can be a pharmaceutically acceptable dry powder havinga particle size in the range of from 5 m to 150 μm; and in certainembodiments in the range of from 35 μm to 80 μm. Suitable binders forrotomelt granulation are low melting point powdered binders, examples ofwhich include: polyethylene glycol 4000, polyethylene glycol 6000,stearic acid, and low melting point waxes. Suitable low melting pointwaxes include but are not limited to glyceryl monostearate, hydrogenatedtallow, myristyl alcohol, myristic acid, stearyl alcohol, substitutedmonoglycerides, substituted diglycerides, substituted triglycerides,white beeswax, carnauba wax, castor wax, japan wax, acetylatemonoglycerides and combinations thereof. The binders can have a meltingpoint of from 30° C. to 100° C.; and in certain embodiments from 40° C.to 85° C.

As a prophetic example of these embodiments that are manufactured by arotomelt granulation process, 320 g of bupropion hydrobromide and 80 gPEG 8000 is dry blended and poured into a Glatt 1.1 chamber set-up as arotary granulator with a longitudinal plate. Inlet air temperature isset to 60° C. and the product chamber heated to approximately 50° C. Theblend is fluidized at approximately 120 m3/hr and the frictional plateset to 900 rpm. The product chamber temperature is raised to 60° C. andthen gradually reduced to 20° C. over a period of approximately 20minutes, during which spheronization is achieved.

Other embodiments of the invention involve the formation of amicroparticle that has a core which includes bupropion hydrobromide anda compound which is sweet in taste and which has a negative heat ofsolution. Examples of compounds falling into this category includemannitol and sorbitol. Sugars or artificial sweeteners to which, forexample, menthol have been added can also work as well. A binder and/orother excipient can also be disposed within the core. The amount ofsweetening compound used can depend on a number of factors including thesize of the resulting microparticles, the size or volume of theresulting tablet, the sturdiness of the microparticle-coatedmicroparticulant, the speed at which the tablet will disintegrate in themouth, the degree of sweetness imparted by the particular sweetenerused, either in the microparticle or in the tablet, or both, the amountof drug used, and the like. For example, particularly ruggedmicroparticles can be less likely to break during chewing and/orcompression. Therefore, the amount of material provided to protectagainst the release of objectionably flavored material can be lessened.In other cases a greater relative amount of sweetening compound can beused. Generally, the amount of sweetening material used will range fromgreater than zero to 80% of the weight of the resulting microparticles.The sweetener and bupropion hydrobromide can be combined in any numberof known ways, such as for example by wet granulation, dry granulation,agglomeration, or spray coating. For example, the sweetener can be usedas an adsorbent for the active agent. Alternatively, particles of eachcan also be simply mixed together. One or more binders, or otheradjuvants can also be used in the formulation of a tablet as well.Binders in these embodiments include, for example: starch (for example,in an amount of from 5% to 10% as an aqueous paste); pregelatinizedstarch (for example, in an amount of 5% to 10% added dry to powder);gelatin (for example, in an amount of from 2% to 10% as an aqueoussolution, or 2% in starch paste); polyvinylpyrrolidone (for example, inan amount of from 2% to 20% in an aqueous or alcoholic solution);methylcellulose (for example, in an amount of from 2% to 10% as anaqueous solution); sodium carboxy methylcellulose (for example, in anamount of from 2% to 10% as an aqueous solution); ethylcellulose (forexample, in an amount of from 5% to 10% as an alcohol or hydroalcoholicsolution); polyacrylamides (Polymer JR) (for example, in an amount offrom 2% to 8% as an aqueous solution); polyvinyloxoazolidone (Devlex)(for example, in an amount of from 5% to 10% as an aqueous orhydroalcoholic solution); and polyvinyl alcohols (for example, in anamount of from 5% to 20% in aqueous solutions). Other adjuvants can alsobe used in forming the core of the microparticles of the presentembodiments of the invention, non-limiting examples of which include:calcium sulfate NF, Dibasic Calcium phosphate NF, Tribasic calciumsulfate NF, starch, calcium carbonate, microcrystalline cellulose,modified starches, lactose, sucrose and the like, STA-RX™, AVICEL™,SOLKA-FLOC™ BW40, alginic acid, EXPLOTAB™, AUTOTAB™, guar gum, kaolinVECGUM™, and bentonite. These adjuvants can be used in up to 20% w/w;and in certain embodiments are present in an amount of from 3% to 5%w/w.

As a prophetic example of these embodiments that have a core comprisingbupropion hydrobromide and a compound which is sweet in taste, bupropionhydrobromide can be granulated using the following procedure:Polyvinylpyrrolidone K-30 USP (240.0 gm) is dissolved into distilledwater (1,890.0 gm) with agitation. Mannitol powder USP (11,160 gm) andbupropion hydrobromide (600.0 gm) are placed in a Zanchetta 50-litergranulator/processor. After an initial two-minute dry mix of the powderswith the chopper on and the propeller adjusted to 200 rpm, thepolyvinylpyrrolidone K-30 solution is slowly sprayed into the mixingpowder bed using an air-driven spray system. The total time ofgranulation including the time of solution addition is approximatelyeight minutes. The granulation end-point is determined visually and bythe consistency of the resulting material. The material is thendischarged onto trays and dried at 80° C. utilizing supplied dry air fora period of six hours to a moisture content of not more than 0.08percent. The dried material is then passed through a hammermill (knivesforward) equipped with a U.S. #40 (420 micron) screen.

Other embodiments of this invention involve the combined granulation andcoating of bupropion hydrobromide into microparticles in which the drugis at least partly located within the microparticle core but capable ofimmediate release. To do this, the bupropion hydrobromide and a granulardisintegrant are first dry-mixed; the powder obtained is thengranulated, in the presence of a mixture of excipients comprising atleast one binder capable of binding the particles together to givegrains; the grains thus formed are then coated by spraying with asuspension comprising at least one coating agent and a membranedisintegrant; and then the coated granules obtained are dried. Thedistinction between the actual granulation and coating steps isrelatively theoretical, insofar as, even though the primary function ofthe binder used in the granulation step is to bind together theparticles, it nevertheless already partially coats the grains formed.Similarly, even though the primary function of the coating agent used inthe actual coating step is to complete the final coating of each of thegrains, it may, however, arbitrarily bind other coated grains by amechanism of granular agglomeration. The binder and the coating agentare chosen from the group comprising cellulose polymers and acrylicpolymers. However, even though the binder and the coating agent arechosen from the same group of compounds, they nevertheless differ fromeach other in their function as previously mentioned. Among thecellulose polymers that can be advantageously chosen are ethylcellulose,hydroxypropylcellulose (HPC), carboxymethylcellulose (CMC) andhydroxypropylmethylcellulose (HPMC), or mixtures thereof. Among theacrylic polymers that can be advantageously chosen are theammonio-methacrylate copolymer (EUDRAGIT® RL or RS), the polyacrylate(EUDRAGIT® NE) and the methacrylic acid copolymer (EUDRAGIT® L or S),EUDRAGIT® being a registered trademark of Rohm. In at least oneembodiment, the binder is of the same nature as the coating agent. Tofurther accelerate the release of the bupropion hydrobromide, thecoating suspension also comprises a permeabilizer which, on account ofits intrinsic solubility properties, causes perforation of the membranecoating, thus allowing the bupropion hydrobromide to be released.Non-limiting examples of permeabilizers include povidone and itsderivatives, polyethylene glycol, silica, polyols and low-viscositycellulose polymers. Polymers of the type such as hypromellose, whoseviscosity is equal to 6 centipoises, are used, for example, aslow-viscosity cellulose polymer. In at least one embodiment, thedry-mixing of initial powder and the granulation, coating and dryingsteps are performed in a fluidized bed. In this case, the initial powdermixture is first fluidized before being granulated by spraying saidpowder with the excipient mixture comprising at least the binder, thegrains obtained then being coated by spraying with the coatingsuspension, the coated granules formed finally being dried in thefluidized bed. In at least one embodiment, the mixture of excipientsused during the granulation step and the coating suspension used duringthe coating step form a single mixture. In this case, the granulationstep can be distinguished from the spraying step by varying differentparameters, such as the rate of spraying of the mixture and theatomization pressure of said mixture. Thus, only some of the mixture ofexcipients is used during the granulation step, while the other portioncan be used during the coating step. Thus, the rate of spraying of thecoating suspension is higher during the granulation step than during thecoating step, whereas the atomization pressure of the coating suspensionis lower during the granulation step than during the coating step. Inpractice, at the laboratory scale in a fluidized-bed device, for exampleof the type such as Glatt GPCG1, during the granulation step, the rateof spraying of the coating suspension is between 10 grams/minute and 25grams/minute, and the atomization pressure is between 1 bar and 1.8 bar.During the coating step, the rate of spraying of the coating suspensionis between 5 grams/minute and 15 grams/minute, while the atomizationpressure is between 1.5 bar and 2.5 bar. In at least one embodiment,between 10% and 20% of the mixture of excipients is sprayed during thegranulation step, the remainder being sprayed during the coating step.

As a prophetic example of these embodiments that involve the combinedgranulation and coating of bupropion hydrobromide into microparticles inwhich the drug is at least partly located within the microparticle corebut capable of immediate release, the microparticles can be manufacturedaccording to the following process: A granulation solution is firstprepared by dissolving 48 g of ethylcellulose in 273 g of ethyl alcohol.A coating suspension is then prepared by mixing 97 g of ethylcellulose,28.5 g of polyethylene glycol 6000, 26 g of sodium croscarmellose, 10 gof precipitated silica and 27.5 g of aspartam in 1900 g of ethylalcohol, until a homogeneous suspension is obtained. The powder mixtureconsisting of 700 grams of bupropion hydrobromide and 35 grams ofAcdisol is then fluidized. The granulation is then started by sprayingthe granulation solution for 15 to 20 minutes at a spraying rate of 25grams/minute and a suspension atomization pressure of 0.8 bar. Theactual coating is then performed by spraying the coating suspension for1 hour 30 minutes at a spraying rate of 15 to 20 grams/minute and asuspension spraying pressure of 1.5 bar.

Other embodiments of the invention involve coating the bupropionhydrobromide material, thereby forming a drug-containing microparticle.One such process for achieving this involves:

(i) Blending and fluidizing a powder mix of active principle and anadjuvant in order to obtain individual grains,

(ii) Separately liquifying under warm conditions a lipid matrix agentcomprising either an ester of behenic acid and alcohol or an ester ofpalmitic/stearic acid and alcohol,

(iii) Coating the fluidized powder mix under warm conditions by sprayingthe lipid matrix agent over the individual grains,

(iv) Lowering the temperature of the combined product in order to allowthe lipid matrix agent to solidify.

This process does not require an evaporation phase or a drying phase,since it does not require a wet-route or solvent-route granulation step,thus making it possible to be freed from any risk due to the presence oftoxic residues in the final product. Furthermore, it is not necessary tocarry out the quantitative determination of the traces of solvents, ananalysis that can be very expensive. According to the process of thisembodiment of the invention, the spraying conditions and thus thecoating characteristics can be modified, in order to vary the releaseprofile of bupropion hydrobromide, by varying several parameters, theadjustment characteristics of which remain simple. Thus, the sprayingair pressure can be increased in order to promote the formation of ahomogeneous film of lipid matrix agent around the grains.Advantageously, the rate of spraying of the lipid matrix agent cansimultaneously be decreased. In this case, the bupropion hydrobromiderelease profile, that is to say a percentage of dissolution as afunction of the time, is obtained which can be low, corresponding to aslow release of the drug. Conversely, the spraying air pressure can bedecreased in order to promote the agglomeration of the grains with oneanother. Advantageously, the rate of spraying of the lipid matrix agentcan simultaneously be increased. In this case, a release profile of thegrains obtained can be obtained which is high, corresponding to a rapidrelease of bupropion hydrobromide. In practice and according to the massof powder employed, the value of the rate of spraying of the lipidmatrix agent can be from two to four times higher when it is desired topromote the agglomeration of the grains with one another than when it isdesired to promote the formation of a homogeneous film around thegrains. On the other hand, the value of the spraying air pressure can befrom one to two times lower when it is desired to promote theagglomeration of the grains with one another than when it is desired topromote the formation of a homogeneous film around the grains. Accordingto the process for manufacturing these embodiments, it is possible,after having determined a given drug release profile, to vary the valuesof spraying air pressure and of spraying rate throughout the coatingstage, making it possible to promote the formation of a homogeneous filmaround the grains or to promote the agglomeration of the grains. Oncethe sequence of the duration of the spraying air pressure and of thespraying rate has been determined, the coating operation can be carriedout continuously and automatically. According to another characteristicof the process of manufacturing these embodiments, the temperature ofthe mixture of liquefied matrix agent and of spraying air is greater by35° C. to 60° C. than the melting temperature of the lipid matrix agent.Likewise, the temperature of the fluidization air and that of the powderis approximately equal to the melting temperature of the lipid matrixagent, plus or minus 10° C. Furthermore, in order to obtain a mixture ofindividual grains, an air-operated fluidized bed device or a turbinedevice can be used. Furthermore, the lipid matrix agent can be sprayedby the air spray technique, that is to say liquid spraying underpressure in the presence of compressed air. According to at least oneembodiment, use is made of a powder comprising the drug and theadjuvant. In other words, after mixing and fluidizing the combinedconstituents of the powder, the lipid matrix agent is sprayed over theindividual grains obtained. In order to avoid adhesion of the coatedgrains obtained, whether in the case where all the grains are treated orwhether in the case where only a portion of the grains is treated, astage of lubrication of the grains is inserted between the coating stageand the stage of putting into a pharmaceutical form. Furthermore, inorder to obtain greater stability of the pharmaceutical composition,that is to say in order to minimize modifications relating to therelease of the bupropion hydrobromide over time, the granules or tabletsobtained in certain embodiments of this example can be subjected to amaturing stage in an oven, for at least 8 hours, at a temperature ofbetween 45° C. and 60° C.; and in certain embodiments at 55° C.

As a prophetic example of these drug-containing microparticleembodiments that are formed by coating the bupropion hydrobromidematerial, the drug-containing microparticles can be manufacturedaccording to the following process: A mixture of powder is preparedcomprising: bupropion hydrobromide; dicalcium phosphate dehydrate; andpolyvinylpyrrolidone. Batches of granules are prepared by a processcomprising the following stages: the mixture of powder obtained issieved; the said powder is mixed, heating while by means of anair-operated fluidized bed, in order to obtain individual grains; thelipid matrix agent (glyceryl behenate, sold under the trade nameCOMPRITOL® 880 ATO) is liquefied separately at 120° C.; the lipid matrixagent is sprayed over the heated powder mixture, and, finally, thetemperature is lowered in order to allow the lipid matrix agent tosolidify. These stages are carried out while varying various parameters,either in order to promote the formation of a homogeneous film aroundthe grains or in order to promote the agglomeration of the grains, inaccordance with the following table:

Parameters Batch 1 Batch 2 Batch 3 Batch 4 % by weight of lipid matrixagent (COMPRITOL ® 888 ATO) 5 4 4 5 Fluidization air flow rate 80 110 8080 (m³/h) Agglomeration Atomization air pressure 2 1.5 1.5 (bar)Temperature of the powder bed 70 70 74 (° C.) Spraying rate forCOMPRITOL ® 42 40 40 (g/min) Coating Atomization air pressure (bar) 2.53.5 2 2 Temperature of the powder bed 70 66 71 70 (° C.) Spraying ratefor COMPRITOL ® 41 20 40 40 (g/min)

Another embodiment of the invention for coating the bupropionhydrobromide material, thereby forming a drug-containing microparticle,involves the formation of coated microcrystals that can subsequently beincorporated into a tablet. Through selection of the appropriate polymerthe microcrystals can possess diversified features such asgastroresistance and controlled release due to the fact that the saidcoated or non-coated microcrystals and microgranules preserve, afterhaving been shaped in the form of a multiparticulate tablet, theirinitial properties amongst which are included masking of taste,gastroresistance and controlled release of the bupropion hydrobromide.In certain embodiments of this example, the following non-limiting listof polymers can be selected for coating of the bupropion hydrobromide inconventional fluidized based coating equipment: ethylcellulose (EC);hydroxypropylcellulose (HPC); hydroxypropylmethylcellulose (HPMC);gelatin; gelatin/acacia; gelatin/acacia/vinvylmethylether maleicanhydride; gelatin/acacia/ethylenemaleic anhydride; carboxymethylcellulose; polyvinvylalcohol; cellulose acetate phthalate;nitrocellulose; shellac; wax; polymethacrylate polymers such asEudragit® RS; Eudragit® RL or combinations of both, Eudragit® E andEudragit NE30D; Kollicoat™ SR30D; and mixtures thereof.

Drug-Layered Microparticles

The drug-layered microparticles can be made by coating an inert particleor core, such as a non-pareil sphere (e.g. sugar sphere), with thebupropion salt and a polymeric binder. In certain embodiments of thedrug-layered microparticles, the inert cores include water-insolublematerials such as cellulose spheres or silicon dioxide. In otherembodiments, the inert cores include water-soluble materials such asstarch, salt or sugar spheres. The inert cores can have a diameterranging from 100 microns to 2000 microns. For example, in certainembodiments the diameter of the inert cores range from 150 microns to1500 microns. In at least one embodiment, the inert cores are sugarspheres NF, containing not less than 62.5% and not more than 91.5% ofsucrose. In at least one embodiment the inert cores have substantiallyconsistent bulk density, low friability, and low dust generationproperties. In at least one embodiment, the inert cores are coated withan osmotic sub-coat comprising an osmotic agent and a polymeric bindingagent. Further, the inert cores can initially be coated with a seal-coatto provide a more consistent core surface and to minimize any osmoticeffects. The seal-coat layer can be applied to the core prior to theapplication of the drug, polymeric binder, and any polymeric filmlayers. In at least one embodiment, the seal-coat layer does notsubstantially modify the release of the bupropion salt. Examples ofsuitable sealants that can be used in the seal-coat include permeable orsoluble agents such as hydroxypropyl methylcellulose, hydroxypropylcellulose, ethylcellulose, a polymethacrylate polymer, hydroxypropylethylcellulose, xanthan gum, and mixtures thereof. In at least oneembodiment the sealant used in the seal-coat is hydroxypropylmethylcellulose. Other agents can be added to improve the processabilityof the sealant. Examples of such agents include talc, colloidal silica,polyvinyl alcohol, titanium dioxide, micronised silica, fumed silica,glycerol monostearate, magnesium trisilicate, magnesium stearate, andmixtures thereof. The seal-coat layer can be applied from solution (e.g.aqueous) or suspension using a fluidised bed coater (e.g. Wurstercoating), or in a pan coating system. Examples of such seal-coatscoatings are commercially available such as those sold under the TradeMarks OPADRY® White Y-1-7000 and OPADRY® OY/B/28920 White, each of whichis available from Colorcon Limited, England.

The binding agent of these drug-layered embodiments is used to adherethe bupropion salt layer to the inert core or seal-coat of the core. Incertain embodiments, the binding agent is water soluble, possessessufficiently high adhesivity in order to adhere the bupropion salt layerto the inert core, and possesses an appropriate viscosity to providesubstantial adhesion between the inert core and the bupropion salt. Inother embodiments the binding agent is water-insoluble. In at least oneembodiment the binding agent is ethyl cellulose, a polymethacrylatepolymer, polyvinylalcohol, polyvinyl pyrrolidone,polyvinylpyrrolidone-vinylacetate copolymer (such as Kollidon VA64),hydroxyethylcellulose, low molecular weight hydroxypropylmethylcellulose(e.g. viscosity of 1-50 cps at 20° C.; 2-12 cps at 20° C.; or 4-6 cps at20° C.), hydroxypropylcellulose polymethacrylates, or mixtures thereof.For example, in certain embodiments the composition of the binder forbupropion hydrobromide is from 1% to 25% w/w; in other embodiments from2% to 10% w/w; and in still other embodiments from 3% to 5% w/w,expressed as a percentage of the total weight of the core.

Solvents can be used to apply the bupropion salt to the inert core,examples of which include lower alcohols such as ethanol, isopropanoland alcohol/water mixtures, acetone and chlorinated hydrocarbons.

The drug-layered microparticles can be prepared by forming a suspensionor solution of the binder and the bupropion salt and then layering thesuspension or solution on to the inert or sub-coated core using any ofthe layering techniques known in the art, such as fluidized bed coatingor pan coating. This can be effected in a single coating or the processcan be carried out in multiple layers, optionally with interveningdrying/evaporation steps. This process can be conducted so as to producemicroparticles containing a desired amount of bupropion salt and achievethe desired dosage and release thereof upon in vivo administration.

In certain embodiments, the drug-layered microparticles can bemanufactured using for example, the procedure in the followinghypothetical experiment: Bupropion hydrobromide (2.8 kg) andhydroxypropyl methylcellulose (METHOCEL® E5) (0.40 kg) is dissolved in amixture of water and isopropyl alcohol. The active drug solution canthen be sprayed onto sugar spheres 30/35 (1.06 kg) in a fluidized bedprocessor with a Wurster insert. The active core microparticles can thenbe dried in a fluidized bed processor until the loss on drying is below1%. The bupropion microparticles can then be passed through a 16 meshscreen and a 30 mesh screen and microparticles can be collected that aresmaller than 16 mesh and larger than 30 mesh.

Microparticle Taste-Masking Coatings

The microparticles of the present invention can each be coated with atleast one taste-masking coating. The taste-masking coating can mask thetaste of the active drug in the microparticles. In at least oneembodiment the taste-masking coating formulations contain polymericingredients. It is contemplated that other excipients consistent withthe objects of the present invention can also be used in thetaste-masking coating.

In at least one embodiment, the taste-masking coating comprises apolymer such as ethylcellulose, which can be used as a dry polymer (suchas ETHOCEL®, Dow Corning) solubilised in organic solvent prior to use,or as an aqueous dispersion. One commercially-available aqueousdispersion of ethylcellulose is AQUACOAT® (FMC Corp., Philadelphia, Pa.,U.S.A.). AQUACOAT® can be prepared by dissolving the ethylcellulose in awater-immiscible organic solvent and then emulsifying the same in waterin the presence of a surfactant and a stabilizer. After homogenizationto generate submicron droplets, the organic solvent is evaporated undervacuum to form a pseudolatex. The plasticizer is not incorporated in thepseudolatex during the manufacturing phase. Thus, prior to using thesame as a coating, the Aquacoat is intimately mixed with a suitableplasticizer prior to use. Another aqueous dispersion of ethylcelluloseis commercially available as SURELEASE® (Colorcon, Inc., West Point,Pa., U.S.A.). This product can be prepared by incorporating plasticizerinto the dispersion during the manufacturing process. A hot melt of apolymer, plasticizer (e.g. dibutyl sebacate), and stabilizer (e.g. oleicacid) is prepared as a homogeneous mixture, which is then diluted withan alkaline solution to obtain an aqueous dispersion which can beapplied directly onto substrates.

In other embodiments, polymethacrylate acrylic polymers can be employedas taste masking polymers. In at least one embodiment, the taste maskingcoating is an acrylic resin lacquer used in the form of an aqueousdispersion, such as that which is commercially available from RohmPharma under the tradename EUDRAGIT® or from BASF under the tradenameKOLLICOAT®. In further preferred embodiments, the acrylic coatingcomprises a mixture of two acrylic resin lacquers commercially availablefrom Rohm Pharma under the tradenames EUDRAGIT® RL and EUDRAGIT® RS,respectively.

EUDRAGIT® RL and EUDRAGIT® RS are copolymers of acrylic and methacrylicesters with a low content of quaternary ammonium groups, the molar ratioof ammonium groups to the remaining neutral (meth)acrylic esters being1:20 in EUDRAGIT® RL and 1:40 in EUDRAGIT® RS. The mean molecular weightis 150,000. The code designations RL (high permeability) and RS (lowpermeability) refer to the permeability properties of these agents.EUDRAGIT® RL/RS mixtures are insoluble in water and in digestive fluids.However, coatings formed from the same are swellable and permeable inaqueous solutions and digestive fluids. EUDRAGIT® RL/RS dispersions orsolutions of the present invention can be mixed together in any desiredratio in order to ultimately obtain a taste masking coating having adesirable drug dissolution profile. Desirable formulations can beobtained, for example, from a coating derived from 100% EUDRAGIT® RL;50% EUDRAGIT® RL with 50% EUDRAGIT® RS; and 10% EUDRAGIT® RL with 90%EUDRAGIT® RS.

In other embodiments, the taste masking polymer can be an acrylicpolymer which is cationic in character based on dimethylaminoethylmethacrylate and neutral methacrylic acid esters (such as EUDRAGIT® E,commercially available from Rohm Pharma). The hydrophobic acrylicpolymer coatings of the present invention can further include a neutralcopolymer based on poly (meth)acrylates, such as EUDRAGIT® NE(NE-neutral ester), commercially available from Rohm Pharma. EUDRAGIT®NE 30D lacquer films are insoluble in water and digestive fluids, butpermeable and swellable.

In other embodiments, the taste masking polymer is a dispersion of poly(ethylacrylate, methyl methacrylate) 2:1 (KOLLICOAT® EMM 30 D, BASF).

In other embodiments, the taste masking polymer can be a polyvinylacetate stabilized with polyvinylpyrrolidone and sodium lauryl sulfatesuch as KOLLICOAT® SR30D (BASF).

Other taste masking polymers include hydroxypropylcellulose (HPC);hydroxypropylmethylcellulose (HPMC); hydroxyethylcellulose; gelatin;gelatin/acacia; gelatin/acacia/vinvylmethylether maleic anhydride;gelatin/acacia/ethylenemaleic anhydride; carboxymethyl cellulose;polyvinvylalcohol; nitrocellulose; polyvinylalcohol-polyethylene glycolgraft-copolymers; shellac; wax and mixtures thereof.

The taste-masking coatings can be applied to the microparticles from oneor more organic or aqueous solvent solutions or suspensions. In at leastone embodiment the organic solvents that can be used to apply thetaste-masking coatings include one or more of acetone, lower alcoholssuch as ethanol, isopropanol and alcohol/water mixtures, chlorinatedhydrocarbons, and the like. Devices used to coat the microparticles ofthe invention with a taste-masking coating include those conventionallyused in pharmaceutical processing, such as fluidized bed coatingdevices. The coatings applied to the microparticles can containingredients other than the functional polymers. One or more colorants,flavorants, sweeteners, can also be used in the taste-masking coating.

In some embodiments a pore former can be included into the taste maskingcoat in order to influence the rate of release of bupropion hydrobromidefrom the microparticle. In other embodiments, a pore former is notincluded in the taste masking coat. The pore formers can be inorganic ororganic, and include materials such as particulate materials that can bedissolved, extracted or leached from the coating in the environment ofuse. Upon exposure to fluids in the environment of use, the pore-formerscan for example be dissolved, and channels and pores are formed thatfill with the environmental fluid.

For example, the pore-formers of certain embodiments can comprise one ormore water-soluble hydrophilic polymers in order to modify the releasecharacteristics of the formulation. Examples of suitable hydrophilicpolymers used as pore-formers include hydroxypropylmethylcellulose,cellulose ethers and protein-derived materials of these polymers, thecellulose ethers, especially hydroxyalkylcelluloses andcarboxyalkylcelluloses. Also, synthetic water-soluble polymers can beused, examples of which include polyvinylpyrrolidone, cross-linkedpolyvinyl-pyrrolidone, polyethylene oxide, water-soluble polydextrose,saccharides and polysaccharides, such as pullulan, dextran, sucrose,glucose, fructose, mannitol, lactose, mannose, galactose, and sorbitol.In at least one embodiment, the hydrophilic polymer compriseshydroxypropyl-methylcellulose.

Other non-limiting examples of pore-formers include alkali metal saltssuch as lithium carbonate, sodium chloride, sodium bromide, potassiumchloride, potassium sulfate, potassium phosphate, sodium acetate, andsodium citrate. The pore-forming solids can also be polymers which aresoluble in the environment of use, such as CARBOWAXES™, and CARBOPOL™.In addition, the pore-formers embrace diols, polyols, polyhydricalcohols, polyalkylene glycols, polyglycols, and poly(a-w)alkylenediols.Other pore-formers which can be useful in the formulations of thepresent invention include starch, modified starch, and starchderivatives, gums, including but not limited to xanthan gum, alginicacid, other alginates, benitoniite, veegum, agar, guar, locust bean gum,gum arabic, quince psyllium, flax seed, okra gum, arabinoglactin,pectin, tragacanth, scleroglucan, dextran, amylose, amylopectin,dextrin, etc., cross-linked polyvinylpyrrolidone, ion-exchange resins,such as potassium polymethacrylate, carrageenan, kappa-carrageenan,lambdacarrageenan, gum karaya, biosynthetic gum, etc. Other pore-formersinclude materials useful for making microporous lamina in theenvironment of use, such as polycarbonates comprised of linearpolyesters of carbonic acid in which carbonate groups reoccur in thepolymer chain, microporous materials such as bisphenol, a microporouspoly(vinylchloride), micro-porous polyamides, microporous modacryliccopolymers, microporous styrene-acrylic and its copolymers, porouspolysulfones, halogenated poly(vinylidene), polychloroethers, acetalpolymers, polyesters prepared by esterification of a dicarboxylic acidor anhydride with an alkylene polyol, poly(alkylenesulfides), phenolics,polyesters, asymmetric porous polymers, cross-linked olefin polymers,hydrophilic microporous hiomopolymers, copolymers or interpolymershaving a reduced bulk density, and other similar materials,poly(urethane), cross-linked chain-extended poly(urethane),poly(imides), poly(benzimidazoles), collodion, regenerated proteins,semi-solid cross-linked poly(vinylpyrrolidone), and mixtures thereof.

In general, the amount of pore-former included in the taste maskingcoatings of certain embodiments of the present invention can be from0.1% to 80%, by weight, relative to the combined weight of polymer andpore-former. The percentage of pore former as it relates to the dryweight of the taste-masking polymer, can have an influence on the drugrelease properties of the coated microparticle. In at least oneembodiment that uses water soluble pore formers such ashydroxypropylmethylcellulose, a taste masking polymer:pore former dryweight ratio of between 10:1 and 1:1 can be present. In certainembodiments the taste masking polymer:pore former dry weight ratio isfrom 8:1 to 1.5:1; and in other embodiments from 6:1 to 2:1. In at leastone embodiment using EUDRAGIT® NE30D as the taste masking polymer and ahydroxypropylmethylcellulose (approx 5 cps viscosity (in a 2% aqueoussolution)) such as METHOCEL® E5, Pharmacoat 606G as the water solublepore former, a taste masking polymer:pore former dry weight ratio of 2:1is present.

Colorants that can be used in the taste-masking coating include food,drug and cosmetic colors (FD&C), drug and cosmetic colors (D&C) orexternal drug and cosmetic colors (Ext. D&C). These colors are dyes,lakes, and certain natural and derived colorants. Useful lakes includedyes absorbed on aluminum hydroxide or other suitable carriers.

Flavorants that can be used in the taste-masking coating include naturaland synthetic flavoring liquids. An illustrative list of such flavorantsincludes volatile oils, synthetic flavor oils, flavoring aromatics,oils, liquids, oleoresins and extracts derived from plants, leaves,flowers, fruits, stems and combinations thereof. A non-limitingrepresentative list of these includes citric oils, such as lemon,orange, grape, lime and grapefruit, and fruit essences, including apple,pear, peach, grape, strawberry, raspberry, cherry, plum, pineapple,apricot, or other fruit flavors. Other useful flavorants includealdehydes and esters, such as benzaldehyde (cherry, almond); citral,i.e., alpha-citral (lemon, lime); neral, i.e., beta-citral (lemon,lime); decanal (orange, lemon); aldehyde C-8 (citrus fruits); aldehydeC-9 (citrus fruits); aldehyde C-12 (citrus fruits); tolyl aldehyde(cherry, almond); 2,6-dimethyloctanal (green fruit); 2-dodenal (citrusmandarin); mixtures thereof and the like.

Sweeteners that can be used in the taste-masking coating include glucose(corn syrup), dextrose, invert sugar, fructose, and mixtures thereof(when not used as a carrier); saccharin and its various salts, such assodium salt; dipeptide sweeteners such as aspartame; dihydrochalconecompounds, glycyrrhizin; Steva Rebaudiana (Stevioside); chloroderivatives or sucrose such as sucralose; and sugar alcohols such assorbitol, mannitol, xylitol, and the like. Also contemplated arehydrogenated starch hydrolysates and the synthetic sweeteners such as3,6-dihydro-6-methyl-1-1-1,2,3-oxathiazin-4-1-2,2-dioxide, particularlythe potassium salt (acesulfame-K), and sodium and calcium salts thereof.The sweeteners can be used alone or in any combination thereof.

The microparticle taste masking coat can also include one or morepharmaceutically acceptable excipients such as lubricants, emulsifiers,anti-foaming agents, plasticisers, solvents and the like.

Lubricants can be included to help reduce friction of coatedmicroparticles during manufacturing. The lubricants that can be used inthe taste masking coat of the present invention include but are notlimited to adipic acid, magnesium stearate, calcium stearate, zincstearate, calcium silicate, magnesium silicate, hydrogenated vegetableoils, sodium chloride, sterotex, polyoxyethylene, glyceryl monostearate,talc, polyethylene glycol, sodium benzoate, sodium lauryl sulfate,magnesium lauryl sulfate, sodium stearyl fumarate, light mineral oil,waxy fatty acid esters such as glyceryl behenate, (i.e. COMPRITOL™),STEAR-O-WET™, MYVATEX™ TL and mixtures thereof. In at least oneembodiment, the lubricant is selected from magnesium stearate and talc.Combinations of these lubricants are operable. The lubricant can each bepresent in an amount of from 1% to 100% by weight of the polymer dryweight in the taste masking coat. For example, in certain embodimentswherein the taste masking polymer is EUDRAGIT® NE30D or EUDRAGIT® NE40D(Rohm America LLC) together with a hydrophilic pore former, thelubricant is present in an amount of from 1% to 30% by weight of thepolymer dry weight; in other embodiments from 2% to 20%; and in stillother embodiments at 10% by weight of the microparticle taste maskingcoat dry weight. In another embodiment where the taste masking polymeris ethylcellulose (ETHOCEL™ PR100, PR45, PR20, PR10 or PR7 polymer, or amixture thereof), the lubricant can be present in an amount of from 10%to 100% by weight of the microparticle taste masking coat dry weight; inanother embodiment from 20% to 80%; and in still another embodiments at50% by weight of the microparticle taste masking coat dry weight. Inother embodiments, the taste masking coat does not include a poreformer.

Emulsifying agent(s) (also called emulsifiers or emulgents) can beincluded in the microparticle taste masking coat to facilitate actualemulsification during manufacture of the coat, and also to ensureemulsion stability during the shelf-life of the product. Emulsifyingagents useful for the microparticle taste masking coat compositioninclude, but are not limited to naturally occurring materials and theirsemi synthetic derivatives, such as the polysaccharides, as well asglycerol esters, cellulose ethers, sorbitan esters (e.g. sorbitanmonooleate or SPAN™ 80), and polysorbates (e.g. TWEEN™ 80). Combinationsof emulsifying agents are operable. In at least one embodiment, theemulsifying agent is TWEEN™ 80. The emulsifying agent(s) can be presentin an amount of from 0.01% to 5% by weight of the microparticle tastemasking polymer dry weight. For example, in certain embodiments theemulsifying agent is present in an amount of from 0.05% to 3%; in otherembodiments from 0.08% to 1.5%, and in still other embodiments at 0.1%by weight of the microparticle taste masking polymer dry weight.

Anti-foaming agent(s) can be included in the microparticle taste maskingcoat to reduce frothing or foaming during manufacture of the coat.Anti-foaming agents useful for the coat composition include, but are notlimited to simethicone, polyglycol, silicon oil, and mixtures thereof.In at least one embodiment the anti-foaming agent is Simethicone C. Theanti-foaming agent can be present in an amount of from 0.1% to 10% ofthe microparticle taste masking coat weight. For example, in certainembodiments the anti-foaming agent is present in an amount of from 0.2%to 5%; in other embodiments from 0.3% to 1%, and in still otherembodiments at 0.6% by weight of the microparticle taste masking polymerdry weight.

Plasticizer(s) can be included in the microparticle taste masking coatto provide increased flexibility and durability during manufacturing.Plasticisers that can be used in the microparticle taste masking coatinclude acetylated monoglycerides; acetyltributyl citrate, butylphthalyl butyl glycolate; dibutyl tartrate; diethyl phthalate; dimethylphthalate; ethyl phthalyl ethyl glycolate; glycerin; propylene glycol;triacetin; tripropioin; diacetin; dibutyl phthalate; acetylmonoglyceride; acetyltriethyl citrate, polyethylene glycols; castor oil;rape seed oil, olive oil, sesame oil, triethyl citrate; polyhydricalcohols, glycerol, glycerin sorbitol, acetate esters, gylceroltriacetate, acetyl triethyl citrate, dibenzyl phthalate, dihexylphthalate, butyl octyl phthalate, diisononyl phthalate, butyl octylphthalate, dioctyl azelate, epoxidized tallate, triisoctyl trimellitate,diethylhexyl phthalate, di-n-octyl phthalate, di-i-octyl phthalate,di-i-decyl phthalate, di-n-undecyl phthalate, di-n-tridecyl phthalate,tri-2-ethylhexyl trimellitate, di-2-ethylhexyl adipate, di-2-ethylhexylsebacate, di-2-ethylhexyl azelate, dibutyl sebacate, diethyloxalate,diethylmalate, diethylfumerate, dibutylsuccinate, diethylmalonate,dibutylphthalate, dibutylsebacate, glyceroltributyrate, and mixturesthereof. The plasticizer can be present in an amount of from 1% to 80%of the taste masking polymer dry weight. For example, in certainembodiments the plasticizer is present in an amount of from 5% to 50%,in other embodiments from 10% to 40%, and in still other embodiments at20% of the taste masking polymer dry weight.

The taste-masking coating can be present in an amount of from 1% to 90%by weight of the microparticle, depending upon the choice of polymer,the ratio of polymer:pore former, and the total surface area of themicroparticle formulation. Since a certain thickness of taste maskingcoating has to be achieved in order to achieve effective taste masking,the amount of taste masking polymer coating used during manufacture isrelated to the total surface area of the batch of uncoatedmicroparticles that requires a coating. The taste masking polymersurface area coverage can range from 0.5 mg/cm2 to 20 mg/cm2. Forexample, in certain embodiments the surface area coverage of the tastemasking polymer is from 0.6 mg/cm2 to 10 mg/cm2, and in otherembodiments is from 1 mg/cm2 to 5 mg/cm2. In at least one embodiment ofthe invention, EUDRAGIT® E is employed as the taste masking polymer at asurface area coverage of 4 mg/cm2. One approach in estimating the totalsurface area of a multiparticulate batch is the permeability methodaccording to Blaine (ASTM Des. C 205-55), which is based upon themathematical model of laminar flow through capillaries arranged inparallel.

In the absence of an accurate determination of total surface area of amicroparticle, the amount of taste masking polymer to be applied can beexpressed as a percentage of the uncoated microparticle. For example, incertain embodiments the taste-masking coating is present in an amount offrom 5% to 60%; in other embodiments from 10% to 40%; and in still otherembodiments from 15% to 35% by weight of the microparticle. In at leastone embodiment the taste-masking coating is present in an amount of 30%by weight of the microparticle.

In certain embodiments, the diameter of the microparticles (with orwithout the taste-masking coating) range from 50 μm to 800 μm. Forexample, in certain embodiments the diameter of the microparticles rangefrom 100 μm to 600 μm, and in other embodiments from 150 μm to 450 μm.

Microparticle Control-Releasing Coat

The microparticles of the present invention can each be coated with atleast one control-releasing coat. As used herein, the term“microparticle control-releasing coat” refers to the control-releasingcoat that substantially surrounds each microparticle. The microparticlecontrol-releasing coat is designed to achieve a controlled release ofthe bupropion salt from the microparticle. For example, themicroparticle control-releasing coat can be an enteric coat with lowsolubility at a gastric pH to reduce or minimize the drug release in thelumen of the stomach, whilst possessing pH dependent solubility tofacilitate drug release in the duodenum. In another embodiment, thecontrol releasing coat can be a delayed release coating that provides adelayed release of the bupropion salt with a predetermined lagtime thatis independent of, or alternatively dependent on, the pH of thedissolution medium. For example, by increasing the thickness of themicroparticle control-releasing coat using a pH independent diffusionpolymer, lagtimes of 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, or 12 hours can beachieved. Alternatively, controlled release polymers can be selectedthat become soluble above a certain pH. Drug release from such a systemis reduced or minimized until the critical pH for the polymer of choiceis exceeded. With either approach, following the predetermined lag, drugis released, for example within 1 hour for an immediate release pulse,or alternatively over a prolonged period of time, for example from 3 to24 hours. In other embodiments, the microparticle control-releasing coatcan provide a diffusion barrier that is independent of pH, thusfacilitating a sustained release profile, with substantially fullrelease of the bupropion salt occurring in from 3 to 24 hours followingadministration. In at least one embodiment, the microparticlecontrol-releasing coat provides a delayed and sustained release of thebupropion salt from the microparticle with substantially full release in24 hours following administration.

In certain embodiments, the microparticle control-releasing coat canprovide substantially full release of the bupropion salt from themicroparticle without requiring the use of any pore formers. Unnecessarypore formers that are not required in the microparticlecontrol-releasing coat include hydrophilic polymers such ashydroxypropyl methylcellulose.

The microparticle control-releasing coat includes at least one polymerin an amount sufficient to achieve a controlled release of the bupropionsalt. In at least one embodiment of the invention the control releasingpolymer is an acrylic polymer. Suitable acrylic polymers include but arenot limited to acrylic acid and methacrylic acid copolymers, methylmethacrylate copolymers, ethoxyethyl methacrylates, cynaoethylmethacrylate, aminoalkyl methacrylate copolymer, poly(acrylic acid),poly(methacrylic acid, methacrylic acid alkylamine copolymer,poly(methyl methacrylate), poly(methacrylic acid) (anhydride), glycidylmethacrylate copolymers, and mixtures thereof.

In at least one embodiment the control-releasing coat comprisespolymerizable quaternary ammonium compounds, of which non-limitingexamples include quaternized aminoalkyl esters and aminoalkyl amides ofacrylic acid and methacrylic acid, for example1-methacryl-oxyethyl-trimethyl-ammonium methosulfate,1-acryloxy-propyl-trimethyl-ammonium chloride, andtrimethylaminomethyl-methacrylamide methosulfate. The quaternaryammonium atom can also be part of a heterocycle, as inmethacryloxyethylmethyl-morpholiniom chloride or the correspondingpiperidinium salt, or it can be joined to an acrylic acid group or amethacrylic acid group by way of a group containing hetero atoms, suchas a polyglycol ether group. Further suitable polymerizable quaternaryammonium compounds include quaternized vinyl-substituted nitrogenheterocycles such as methyl-vinyl pyridinium salts, vinyl esters ofquaternized amino carboxylic acids, and styryltrialkyl ammonium salts.Other polymerizable quaternary ammonium compounds useful in the presentinvention include acryl- and methacryl-oxyethyltrimethyl-ammoniumchloride and methosulfate, benzyldimethylammoniumethyl-methacrylatechloride, diethylmethylammoniumethyl-acrylate and -methacrylatemethosulfate, N-trimethylammoniumpropylmethacrylamide chloride, andN-trimethylammonium-2,2-dimethylpropyl-1-methacrylate chloride.

In at least one embodiment, the polymer of the control-releasing coat isan acrylic polymer comprised of one or more ammonio methacrylatecopolymers. Ammonio methacrylate copolymers (such as those sold underthe Trade Mark EUDRAGIT® RS and RL) are described in NF XVII as fullypolymerized copolymers of acrylic and methacrylic acid esters with a lowcontent of quaternary ammonium groups. In order to obtain a desirabledissolution profile for a given therapeutically active agent such asbupropion hydrobromide, it may be necessary in some embodiments toincorporate two or more ammonio methacrylate copolymers having differingphysical properties. For example, it is known that by changing the molarratio of the quaternary ammonium groups to the neutral (meth)acrylicesters, the permeability properties of the resultant control-releasingcoat can be modified.

In other embodiments of the present invention, the acrylic polymercoating further includes a polymer whose permeability is pH dependent,such as anionic polymers synthesized from methacrylic acid andmethacrylic acid methyl ester. Such polymers are commercially available,e.g., from Rohm Pharma GmbH under the tradename EUDRAGIT® L andEUDRAGIT® S, and the ratio of free carboxyl groups to the esters is saidto be 1:1 in EUDRAGIT® L and 1:2 in EUDRAGIT® S. EUDRAGIT® L isinsoluble in acids and pure water, but becomes increasingly permeableabove pH 5.0. EUDRAGIT® S is similar, except that it becomesincreasingly permeable above pH 7. The hydrophobic acrylic polymercoatings can also include a polymer which is cationic in character basedon dimethylaminoethyl methacrylate and neutral methacrylic acid esters(such as EUDRAGIT® E, commercially available from Rohm Pharma). Thehydrophobic acrylic polymer coatings of certain embodiments can furtherinclude a neutral copolymer based on poly (meth)acrylates, such asEUDRAGIT® NE (NE=neutral ester), commercially available from RohmPharma. EUDRAGIT® NE 30D lacquer films are insoluble in water anddigestive fluids, but permeable and swellable.

In other embodiments of the invention the control-releasing polymer is adispersion of poly (ethylacrylate, methyl methacrylate) 2:1 (KOLLICOAT®EMM 30 D, BASF). In other embodiments the control releasing polymer canbe a polyvinyl acetate stabilized with polyvinylpyrrolidone and sodiumlauryl sulfate such as KOLLICOAT® SR30D (BASF). The dissolution profilecan be altered by changing the relative amounts of different acrylicresin lacquers included in the coating. Also, by changing the molarratio of polymerizable permeability-enhancing agent (e.g., thequaternary ammonium compounds) in certain embodiments to the neutral(meth)acrylic esters, the permeability properties (and thus thedissolution profile) of the resultant coating can be modified.

In at least one embodiment the control releasing polymer isethylcellulose, which can be used as a dry polymer (such as ETHOCEL®,Dow Corning) solubilised in organic solvent prior to use, or as anaqueous dispersion. One commercially available aqueous dispersion ofethylcellulose is AQUACOAT® (FMC Corp., Philadelphia, Pa., U.S.A.).AQUACOAT® can be prepared by dissolving the ethylcellulose in awater-immiscible organic solvent and then emulsifying the same in waterin the presence of a surfactant and a stabilizer. After homogenizationto generate submicron droplets, the organic solvent is evaporated undervacuum to form a pseudolatex. The plasticizer is not incorporated in thepseudolatex during the manufacturing phase. Thus, prior to using thesame as a coating, the AQUACOAT® is intimately mixed with a suitableplasticizer prior to use. Another aqueous dispersion of ethylcelluloseis commercially available as SURELEASE® (Colorcon, Inc., West Point,Pa., U.S.A.). This product can be prepared by incorporating aplasticizer into the dispersion during the manufacturing process. A hotmelt of a polymer, plasticizer (e.g. dibutyl sebacate), and stabilizer(e.g. oleic acid) is prepared as a homogeneous mixture, which is thendiluted with an alkaline solution to obtain an aqueous dispersion whichcan be applied directly onto substrates.

Other examples of polymers that can be used in the microparticlecontrol-releasing coat include cellulose acetate phthalate, celluloseacetate trimaletate, hydroxy propyl methylcellulose phthalate, polyvinylacetate phthalate, polyvinyl alcohol phthalate, shellac; hydrogels andgel-forming materials, such as carboxyvinyl polymers, sodium alginate,sodium carmellose, calcium carmellose, sodium carboxymethyl starch, polyvinyl alcohol, hydroxyethyl cellulose, methyl cellulose, ethylcellulose, gelatin, starch, and cellulose based cross-linked polymers inwhich the degree of crosslinking is low so as to facilitate adsorptionof water and expansion of the polymer matrix, hydroxypropyl cellulose,hydroxypropyl methylcellulose, polyvinylpyrrolidone, crosslinked starch,microcrystalline cellulose, chitin, pullulan, collagen, casein, agar,gum arabic, sodium carboxymethyl cellulose, (swellable hydrophilicpolymers) poly(hydroxyalkyl methacrylate) (molecular weight 5 k to 5000k), polyvinylpyrrolidone (molecular weight 10 k to 360 k), anionic andcationic hydrogels, zein, polyamides, polyvinyl alcohol having a lowacetate residual, a swellable mixture of agar and carboxymethylcellulose, copolymers of maleic anhydride and styrene, ethylene,propylene or isobutylene, pectin (molecular weight 30 k to 300 k),polysaccharides such as agar, acacia, karaya, tragacanth, algins andguar, polyacrylamides, POLYOX® polyethylene oxides (molecular weight 100k to 5000 k), AQUAKEEP® acrylate polymers, diesters of polyglucan,crosslinked polyvinyl alcohol and poly N-vinyl-2-pyrrolidone,hydrophilic polymers such as polysaccharides, methyl cellulose, sodiumor calcium carboxymethyl cellulose, hydroxypropyl methyl cellulose,hydroxypropyl cellulose, hydroxyethyl cellulose, nitro cellulose,carboxymethyl cellulose, cellulose ethers, methyl ethyl cellulose,ethylhydroxy ethylcellulose, cellulose acetate, cellulose butyrate,cellulose propionate, gelatin, starch, maltodextrin, pullulan, polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl acetate, glycerol fatty acidesters, polyacrylamide, polyacrylic acid, natural gums, lecithins,pectin, alginates, ammonia alginate, sodium, calcium, potassiumalginates, propylene glycol alginate, agar, and gums such as arabic,karaya, locust bean, tragacanth, carrageens, guar, xanthan, scleroglucanand mixtures and blends thereof.

In at least one embodiment the control-releasing coat of themicroparticles comprises polymers that can facilitate mucoadhesionwithin the gastrointestinal tract. Non-limiting examples of polymersthat can be used for mucoadhesion include carboxymethylcellulose,polyacrylic acid, CARBOPOL™, POLYCARBOPHIL™, gelatin and other naturalor synthetic polymers.

In at least one embodiment the microparticles are coated with acontrol-releasing coat comprised of:

(i) at least one film-forming polymer which is insoluble in the liquidsof the digestive tract, present in an amount of from 50% to 90% (e.g.from 50% to 80%) by weight of dry matter of the control-releasing coatcomposition, and including at least one non-hydrosoluble cellulosederivate, (e.g. ethylcellulose, cellulose acetate, or mixtures thereof);

(ii) at least one nitrogen-containing polymer, present in an amount offrom 2% to 25% (e.g. from 5% to 15%) by weight of dry matter of thecontrol-releasing coat composition, and including at least onepolyacrylamide, poly-N-vinylaride, poly-N-vinyl-lactame,polyvinylpyrrolidone, or mixtures thereof;

(iii) optionally at least one plasticizer present in an amount of from2% to 20% (e.g. from 4% to 15%) by weight of dry matter of thecontrol-releasing coat composition, and including at least one of thefollowing compounds: glycerol esters, phtalates, citrates, sebacates,cetylalcohol esters, castor oil, cutin, or mixtures thereof;

(iv) at least one surface-active and/or lubricating agent, present in anamount of from 2% to 20% (e.g. from 4% to 15%) by weight of dry matterof the control-releasing coat composition, and chosen from anionicsurfactants such as the alkali metal and alkaline-earth metal salts offatty acids, (e.g. stearic acid, oleic acid, and mixtures thereof),and/or from nonionic surfactants such as polyoxyethylenated esters ofsorbitan, polyoxyethylenated esters of sorbitan, polyoxyethylenatedderivatives of castor oil, and/or from lubricants such as stearates(e.g. calcium, magnesium, aluminum, zinc stearate and mixtures thereof),stearylfumarates (e.g. sodium stearylfumarate, glyceryl behenate andmixtures thereof); and mixtures thereof; wherein the coatedmicroparticles are designed so as to be able to remain in the smallintestine for a period of at least 5 hours; in certain embodiments atleast 7 hours; and in certain other embodiments for a period of between8 hours and 24 hours; so as to allow absorption of the bupropionhydrobromide during at least part of its time in the small intestine.

In a prophetic example of this embodiment of the invention, themicroparticles are coated in a fluidized bead coater with the followingcoating solution:

Ethylcellulose 44.7 g PVP 4.8 g Castor oil 4.8 g Magnesium Stearate 6.1g Acetone 479 g Isopranol 53 g

In other embodiments of the present invention, the release of thebupropion hydrobromide from a controlled release formulation can befurther influenced, i.e., adjusted to a desired rate, by the addition ofone or more pore-formers to the control-releasing coat, where thepore-formers can be inorganic or organic, and can include materials thatcan be dissolved, extracted or leached from the control-releasing coatin the environment of use. Upon exposure to fluids in the environment ofuse, the pore-formers are, for example, dissolved, and channels andpores are formed that fill with the environmental fluid. For example,the pore-formers can include one or more water-soluble hydrophilicpolymers in order to modify the release characteristics of theformulation. Non-limiting examples of suitable hydrophilic polymersinclude hydroxypropylmethylcellulose, cellulose ethers andprotein-derived materials of these polymers, the cellulose ethers, (e.g.hydroxyalkylcelluloses and carboxyalkylcelluloses), and mixturesthereof. Also, synthetic water-soluble polymers can be used, such aspolyvinylpyrrolidone, cross-linked polyvinyl-pyrrolidone, polyethyleneoxide, water-soluble polydextrose, saccharides and polysaccharides, suchas pullulan, dextran, sucrose, glucose, fructose, mannitol, lactose,mannose, galactose, sorbitol, and mixtures thereof. In at least oneembodiment the hydrophilic polymer(s) includehydroxypropyl-methylcellulose. Other examples of pore-formers includealkali metal salts such as lithium carbonate, sodium chloride, sodiumbromide, potassium chloride, potassium sulfate, potassium phosphate,sodium acetate, sodium citrate, and mixtures thereof. The pore-formingsolids can also be polymers which are soluble in the environment of use,such as CARBOWAXES®, CARBOPOL®, and the like. The possible pore-formersembrace diols, polyols, polyhydric alcohols, polyalkylene glycols,polyglycols, poly(a-w)alkylenediols, and mixtures thereof. Otherpore-formers which can be useful in the formulations of the presentinvention include starch, modified starch, and starch derivatives, gums,including but not limited to xanthan gum, alginic acid, other alginates,benitoniite, veegum, agar, guar, locust bean gum, gum arabic, quincepsyllium, flax seed, okra gum, arabinoglactin, pectin, tragacanth,scleroglucan, dextran, amylose, amylopectin, dextrin, etc., cross-linkedpolyvinylpyrrolidone, ion-exchange resins, such as potassiumpolymethacrylate, carrageenan, kappa-carrageenan, lambda-carrageenan,gum karaya, biosynthetic gum, and mixtures thereof. Other pore-formersinclude materials useful for making microporous lamina in theenvironment of use, such as polycarbonates comprised of linearpolyesters of carbonic acid in which carbonate groups reoccur in thepolymer chain, microporous materials such as bisphenol, a microporouspoly(vinylchloride), micro-porous polyamides, microporous modacryliccopolymers, microporous styrene-acrylic and its copolymers, porouspolysulfones, halogenated poly(vinylidene), polychloroethers, acetalpolymers, polyesters prepared by esterification of a dicarboxylic acidor anhydride with an alkylene polyol, poly(alkylenesulfides), phenolics,polyesters, asymmetric porous polymers, cross-linked olefin polymers,hydrophilic microporous hiomopolymers, copolymers or interpolymershaving a reduced bulk density, and other similar materials,poly(urethane), cross-linked chain-extended poly(urethane),poly(imides), poly(benzimidazoles), collodion, regenerated proteins,semi-solid cross-linked poly(vinylpyrrolidone), and mixtures thereof.

In other embodiments a surfactant or an effervescent base can beincluded in the control-releasing coat, which can reduce and in certainembodiments overcome surface tension effects. In addition, thecontrol-releasing coat of certain embodiments can include one or moreosmagents (i.e., which can osmotically deliver the active agent from thedevice by providing an osmotic pressure gradient against the externalfluid), swelling agents (i.e., which can include, but are not limited tohydrophilic pharmaceutically acceptable compounds with various swellingrates in water), or other pharmaceutically acceptable agents (i.e.,provided in an amount sufficient to facilitate the entry of theenvironmental fluid without causing the disruption of the impermeablecoating). The surfactants that can be used in the control-releasing coatof certain embodiments can be anionic, cationic, nonionic, oramphoteric. Non-limiting examples of such surfactants include sodiumlauryl sulfate, sodium dodecyl sulfate, sorbitan esters, polysorbates,pluronics, potassium laurate, and mixtures thereof. Non-limitingexamples of effervescent bases that can be used in the control-releasingcoat of certain embodiments include sodium glycine carbonate, sodiumcarbonate, potassium carbonate, sodium bicarbonate, potassiumbicarbonate, calcium bicarbonate, and mixtures thereof. Non-limitingexamples of osmagents that can be used in the control-releasing coat ofcertain embodiments include sodium chloride, calcium chloride, calciumlactate, sodium sulfate, lactose, glucose, sucrose, mannitol, urea,other organic and inorganic compounds known in the art, and mixturesthereof. The swelling agent can include, but is not limited to at leastone pharmaceutically acceptable hydrophilic compound, having a swellingrate or swelling amount in water at 25° C. that is: greater than orequal to at least 10% by weight (wt/wt), greater than or equal to atleast 15% by weight (wt/wt), or greater than or equal to at least 20% byweight (wt/wt). Non-limiting examples of swelling agents that can beused in the control-releasing coat of certain embodiments of the presentinvention include crosslinked polyvinylpyrrolidones (e.g. polyplasdone,crospovidone and mixtures thereof), crosslinked carboxyalkylcelluloses,crosslinked carboxymethylcellulose (e.g. crosslinked sodiumcroscarmellose), hydrophilic polymers of high molar mass (i.e., whichcan be, but are not limited to being greater than or equal to 100,000Daltons) which can include, but are not limited to:polyvinylpyrrolidone(s), polyalkylene oxides (e.g. polyethylene oxide,polypropylene oxide, and mixtures thereof), hydroxyalkylcelluloses (e.g.hydroxypropylcellulose, hydroxypropylmethylcellulose and mixturesthereof), carboxyalkylcellulose (e.g. carboxymethylcellulose), modifiedstarch (e.g. sodium glycolate), starch or natural starch (e.g. corn,wheat, rice, potato and mixtures thereof), cellulose (i.e. which can be,but is not limited to being in powder form or microcrystalline form),sodium alginate, potassium polacriline, and corresponding blends ormixtures thereof. In other embodiments, non-limiting examples of theswelling agent include the following sub-set of compounds: crosslinkedpolyvinylpyrrolidone (e.g. polyplasdone, crospovidone or mixturesthereof), crosslinked carboxyalkylcelluloses (e.g. crosslinkedcarboxymethylcelluloses such as crosslinked sodium croscarmellose), andmixtures thereof. In other embodiments, the swelling agent can be anitrogen containing polymer, non-limiting examples of which can includepolyvinylpyrrolidone, crosslinked polyvinylpyrrolidone and mixturesthereof. The concentration of the swelling agent in thecontrol-releasing coat of certain embodiments of the present inventioncan be from 3% to 40% by weight of the microparticle. For example, incertain embodiments the concentration of the swelling agent in thecontrol-releasing coat is from 4% to 30%, and in other embodiments from5% to 25% by weight of the microparticle.

In certain embodiments one or more pharmaceutically acceptableexcipients consistent with the objects of the present invention can beused in the control-releasing coat, such as a lubricant, an emulsifyingagent, an anti-foaming agent, and/or a plasticizer.

Lubricants can be included in the control-releasing coat to help reducefriction of coated microparticles during manufacturing. The lubricantsthat can be used in the control-releasing coat of certain embodiments ofthe present invention include but are not limited to adipic acid,magnesium stearate, calcium stearate, zinc stearate, calcium silicate,magnesium silicate, hydrogenated vegetable oils, sodium chloride,sterotex, polyoxyethylene, glyceryl monostearate, talc, polyethyleneglycol, sodium benzoate, sodium lauryl sulfate, magnesium laurylsulfate, sodium stearyl fumarate, light mineral oil, waxy fatty acidesters such as glyceryl behenate, (e.g. COMPRITOL™), STEAR-O-WET™ andMYVATEX™ TL. In at least one embodiment, the lubricant is selected frommagnesium stearate, talc and mixtures thereof. Combinations of theselubricants are operable. The lubricant can each be present in an amountof from 1% to 100% by weight of the control releasing coat dry weight.For example, in certain embodiments wherein the control release polymeris EUDRAGIT® NE30D or EUDRAGIT® NE40D (Rohm America LLC) together with ahydrophilic pore former, the lubricant is present in an amount of from1% to 30% by weight of the control-releasing coat dry weight; in otherembodiments from 2% to 20%; and in still other embodiments at 10% byweight of the microparticle control-releasing coat dry weight. Inanother embodiments where the control-release polymer is ethylcellulose(ETHOCEL™ PR100, PR45, PR20, PR10 or PR7 polymer, or a mixture thereof),the lubricant can be present in an amount of from 10% to 100% by weightof the microparticle control-releasing coat dry weight; in anotherembodiment from 20% to 80%; and in still another embodiments at 50% byweight of the microparticle control-releasing coat dry weight.

Emulsifying agent(s) (also called emulsifiers or emulgents) can beincluded in the microparticle control-releasing coat to facilitateactual emulsification during manufacture of the coat, and also to ensureemulsion stability during the shelf-life of the product. Emulsifyingagents useful for the microparticle control-releasing coat compositioninclude, but are not limited to naturally occurring materials and theirsemi synthetic derivatives, such as the polysaccharides, as well asglycerol esters, cellulose ethers, sorbitan esters (e.g. sorbitanmonooleate or SPAN™ 80), and polysorbates (e.g. TWEEN™ 80). Combinationsof emulsifying agents are operable. In at least one embodiment, theemulsifying agent is TWEEN™ 80. The emulsifying agent(s) can be presentin an amount of from 0.01% to 5% by weight of the microparticle controlreleasing coat dry weight. For example, in certain embodiments theemulsifying agent is present in an amount of from 0.05% to 3%; in otherembodiments from 0.08% to 1.5%, and in still other embodiments at 0.1%by weight of the microparticle control-releasing coat dry weight.

Anti-foaming agent(s) can be included in the microparticlecontrol-releasing coat to reduce frothing or foaming during manufactureof the coat. Anti-foaming agents useful for the coat compositioninclude, but are not limited to simethicone, polyglycol and silicon oil.In at least one embodiment the anti-foaming agent is Simethicone C. Theanti-foaming agent can be present in an amount of from 0.1% to 10% ofthe microparticle control-releasing coat weight. For example, in certainembodiments the anti-foaming agent is present in an amount of from 0.2%to 5%; in other embodiments from 0.3% to 1%, and in still otherembodiments at 0.6% by weight of the microparticle control-releasingcoat dry weight.

Plasticizer(s) can be included in the microparticle control-releasingcoat to modify the properties and characteristics of the polymers usedin the coat for convenient processing during manufacturing (e.g. provideincreased flexibility and durability during manufacturing). As usedherein, the term “plasticizer” includes any compounds capable ofplasticizing or softening a polymer or binder used in the presentinvention. Once the coat has been manufactured, certain plasticizers canfunction to increase the hydrophilicity of the coat in the environmentof use. During manufacture of the coat, the plasticizer can lower themelting temperature or glass transition temperature (softening pointtemperature) of the polymer or binder. The addition of a plasticizer,such as low molecular weight PEG, generally broadens the averagemolecular weight of a polymer in which they are included therebylowering its glass transition temperature or softening point.Plasticizers can also generally reduce the viscosity of a polymer.Non-limiting examples of plasticisers that can be used in themicroparticle control-releasing coat include acetylated monoglycerides;acetyltributyl citrate, butyl phthalyl butyl glycolate; dibutyltartrate; diethyl phthalate; dimethyl phthalate; ethyl phthalyl ethylglycolate; glycerin; propylene glycol; triacetin; tripropioin; diacetin;dibutyl phthalate; acetyl monoglyceride; acetyltriethyl citrate,polyethylene glycols; castor oil; rape seed oil, olive oil, sesame oil,triethyl citrate; polyhydric alcohols, glycerol, glycerin sorbitol,acetate esters, gylcerol triacetate, acetyl triethyl citrate, dibenzylphthalate, dihexyl phthalate, butyl octyl phthalate, diisononylphthalate, butyl octyl phthalate, dioctyl azelate, epoxidized tallate,triisoctyl trimellitate, diethylhexyl phthalate, di-n-octyl phthalate,di-i-octyl phthalate, di-i-decyl phthalate, di-n-undecyl phthalate,di-n-tridecyl phthalate, tri-2-ethylhexyl trimellitate, di-2-ethylhexyladipate, di-2-ethylhexyl sebacate, di-2-ethylhexyl azelate, dibutylsebacate, diethyloxalate, diethylmalate, diethylfumerate,dibutylsuccinate, diethylmalonate, dibutylphthalate, dibutylsebacate,glyceroltributyrate, and mixtures thereof. The plasticizer can bepresent in an amount of from 1% to 80% of the control-releasing coat dryweight. For example, in certain embodiments the plasticizer is presentin an amount of from 5% to 50%, in other embodiments from 10% to 40%,and in still other embodiments at 20% of the control-releasing coat dryweight.

The control releasing coat can be present in an amount of from 1% to100% by weight of the microparticle, depending upon the choice ofpolymer, the ratio of polymer:pore former, and the total surface area ofthe microparticle formulation. Since a certain thickness of controlrelease coating has to be achieved in order to achieve the desireddissolution profile, the amount of polymer coating required duringmanufacture is related to the total surface area of the batch ofuncoated microparticles that requires a coating. The control releasingpolymer surface area coverage can range from 0.5 mg/cm2 to 30 mg/cm2.For example in certain embodiments the surface area coverage of thecontrol-releasing polymer is from 0.6 mg/cm2 to 20 mg/cm2, and in otherembodiments from 1 mg/cm2 to 5 mg/cm2. In at least one embodiment of theinvention, EUDRAGIT® NE30D is used as the control releasing polymer at asurface area coverage of 10 mg/cm2. One approach to estimate the totalsurface area of a multiparticulate batch is the permeability methodaccording to Blaine (ASTM Des. C 205-55), which is based upon themathematical model of laminar flow through capillaries arranged inparallel. In the absence of an accurate determination of total surfacearea of a microoarticle, the amount of control releasing polymer to beapplied can be expressed as a percentage of the uncoated microparticle.

The control-releasing polymer can be present in an amount of from 1% to99% by weight of the coated microparticle, depending on the controlledrelease profile desired. For example, in certain embodiments the polymeris present in an amount of from 5% to 80%, and in other embodiments from10% to 50% by weight of the coated microparticle. In at least oneembodiment wherein the control-releasing polymer is EUDRAGIT® NE30D,EUDRAGIT® NE40D (Rohm America LLC), KOLLICOAT® SR 30D, or a mixturethereof, the polymer is present in an amount of from 1% to 50%; in otherembodiments from 5% to 30%; and in still other embodiments is 15% byweight of the coated microparticle. In at least one embodiment whereinthe control-releasing polymer is ethylcellulose, the polymer is presentin an amount of from 1% to 99% by weight of the coated microparticle; inother embodiments from 5% to 50%; and in still other embodiments at 20%by weight of the coated microparticle. In at least one embodimentwherein the control-releasing polymer is ETHOCEL™, an ethyl cellulosegrade PR100, PR45, PR20, PR10, PR7 polymer, or a mixture thereof, thepolymer is present in an amount of from 5% to 30% by weight of thecoated microparticle; in other embodiments from 10%0/to 25%; and instill other embodiments at 20% by weight of the coated microparticle.

In certain embodiments, the diameter of the microparticles (with orwithout the control releasing coat) can range from 50 μm to 800 μm. Forexample, in certain embodiments the diameter of the microparticles rangefrom 100 μm to 600 μm, and in other embodiments from 150 μm to 450 μm.

It is contemplated that in alternative embodiments, other excipientsconsistent with the objects of the present invention can also be used inthe microparticle control-releasing coat.

In at least one embodiment, the microparticle control-releasing coatincludes 96% EUDRAGIT® NE30D, 1.9% Magnesium stearate, 1.9% Talc, 0.04%Tween 80, and 0.19% Simethicone C, when expressed as percentage byweight of the dry control-releasing coat composition. In anotherembodiment, the microparticle control-releasing coat includes 68%ethylcellulose, 17% glyceryl monostearate and 15% acetyl tributylcitratewhen expressed as percentage by weight of the dry control-releasing coatcomposition.

The manufacturing process for the microparticle control-releasing coatcan be as follows. Water is split into two portions of 15% and 85%. Theanti-foaming agent and the emulsifying agent are then added to the 15%water portion, and mixed at 300 rpm to form portion A. In at least oneembodiment, the anti-foaming agent is Simethicone C, and the emulsifyingagent is TWEEN™ 80. A first lubricant is then added to the 85% waterportion and mixed at 9500 rpm to form portion B. In at least oneembodiment, the first lubricant is talc. Then portion A is mixed withportion B, a second lubricant is slowly added, and mixed at 700 rpmovernight. In at least one embodiment, the second lubricant is magnesiumstearate. Finally, an aqueous dispersion of a neutral ester copolymer isadded and mixed for 30 minutes at 500 rpm. In at least one embodiment,the aqueous dispersion of a neutral ester copolymer is EUDRAGIT® NE30D.The resultant control-releasing coat solution can then be used to coatthe microparticles to a 35% weight gain with the following parameters:An inlet temperature of from 10° C. to 60° C., preferably from 20° C. to40° C., and more preferably from 25° C. to 35° C.; an outlet temperatureof from 10° C. to 60° C., preferably from 20° C. to 40° C., and morepreferably from 25° C. to 35° C.; a product temperature of from 10° C.to 60° C., preferably from 15° C. to 35° C., and more preferably from22° C. to 27° C.; an air flow of from 10 cm/h to 180 cm/h, preferablyfrom 40 c·m/h to 120 c·m/h, and more preferably from 60 cm/h to 80 cm/h;and an atomizing pressure of from 0.5 bar to 4.5 bar, preferably from 1bar to 3 bar, and more preferably 2 bar. The resultant control-releasingcoated microparticles can then be discharged from the coating chamberand ovencured with the following parameters: A curing temperature offrom 20° C. to 65° C., preferably from 30° C. to 55° C., and morepreferably 40° C.; and a curing time of from 2 hours to 120 hours,preferably from 10 hours to 40 hours, and more preferably 24 hours. Anyother technology resulting in the formulation of the microparticlecontrol-releasing coat consistent with the objects of the invention canalso be used.

3.2.4 Microparticle Dosage Forms

Highly useful dosage forms result when microparticles made fromcompositions containing a bupropion salt, spheronization aids, and otherexcipient(s) are coated with control-releasing polymer(s). Thecontrol-releasing coated microparticles can then be combined with anexcipient mass and/or other pharmaceutical excipients, and compressedinto tablets. Conventional tablets can be manufactured by compressingthe coated microparticles with suitable excipients using knowncompression techniques. The dissolution profile of the control-releasingcoated multiparticles is not substantially affected by the compressionof the microparticles into a tablet. The resultant dosage forms enjoythe processing ease associated with the use of excipient masses and therelease properties associated with control-releasing coatedmicroparticles. Alternatively, the coated microparticles can be filledinto capsules.

The forms of administration according to the invention are suitable fororal administration. In certain embodiments the forms of administrationare tablets and capsules. However, the composition of the invention canalso take the form of pellets, beads or microtablets, which can then bepackaged into capsules or compressed into a unitary solid dosage form.Other solid oral dosage forms as disclosed herein can be prepared by theskilled artisan, despite the fact that such other solid oral dosageforms may be more difficult to commercially manufacture.

The present invention also contemplates combinations of differentlycoated microparticles into a dosage form to provide a variety ofdifferent release profiles. For example, in certain embodiments,microparticles with a delayed release profile can be combined with othermicroparticles having a sustained release profile to provide a multiplecomponent controlled release bupropion formulation. In addition, otherembodiments can include one or more further components of immediaterelease bupropion. The immediate release bupropion component can takethe form of uncoated bupropion microparticles or powders; bupropionmicroparticles coated with a highly soluble immediate release coating,such as an OPADRY® type coating, as are known to those skilled in theart, or a combination of any of the foregoing. The multiple componentscan then be blended together in the desired ratio and placed in acapsule, or formed into a tablet. Examples of multiple componentcontrolled release bupropion formulations are described in U.S. Pat. No.6,905,708.

3.2.5 Dose Sipping Technology

The present invention also contemplates an oral delivery system fordelivering microparticles containing bupropion hydrobromide in admixturewith a fluid. For example, an oral delivery system is provided whichcomprises a hollow drug formulation chamber. In at least one embodiment,the chamber has a first end and a second end and contains a formulationin the form of microparticles. In at least one embodiment, the drugformulation comprises bupropion hydrobromide. The system furthercomprises a fluid passing drug formulation retainer in the first end ofthe chamber. The retainer prevents release of the microparticles fromthe first end while permitting fluid entry into the chamber. In otherembodiments, the microparticles contained within the chamber comprisebupropion hydrobromide and at least one other drug.

The present invention further provides a method for orally deliveringmicroparticles containing bupropion hydrobromide formulation inadmixture with a fluid. The method involves inserting microparticles ofbupropion hydrobromide formulation into a hollow drug delivery chamberof a drug delivery device. The chamber has a first end and a second end.The first end of the chamber has a fluid passing drug formulationretainer. The drug delivery device has a first and second end. The firstend of the drug delivering device is inserted into a fluid and thesecond end is inserted into the mouth of a patient. The patient thenapplies suction to the second end of the device to cause delivery of thefluid and microparticles of bupropion hydrobromide formulation into thepatient's mouth.

The term “drug formulation retainer” as used herein, refers to a valve,plug or restriction, or the like that prevents passage of the drugformulation from the device. By “fluid passing drug formulationretainer” is intended a valve, plug or restriction or the like thatallows for passage of fluids but does not allow for passage of otheringredients such as the drug formulation that is contained in thedelivery device.

The dispensing device of this embodiment of the invention finds usewhere it is inconvenient or unsafe to use solid oral dosage forms suchas capsules or tablets. The devices can be particularly useful ingeriatric or pediatric patient populations but they can also be usefulfor those who have difficulty swallowing capsules or tablets. A singledelivery device or several devices can be administered to a patientduring a therapeutic program.

Generally the device is in prepared form prior to placement in a fluid.In at least one embodiment the dispensing device comprises a hollow drugformulation chamber with a first end and a second end. Contained withinthe chamber are drug formulation and fluid passing drug formulationretainers. The fluid passing drug formulation retainer comprises arestriction and a one-way plug. The diameter of the opening is smallerthan the plug. In at least one embodiment the restriction is made bycrimping an end of the chamber. The second end of the chamber has a drugformulation retainer for preventing release of the plug. In at least oneembodiment the retainer is prepared by crimping the end of the chamber.Microparticles of bupropion hydrobromide are then placed in the chamber.An end-cap is placed over the second end of the chamber prior to use toprevent release of the drug formulation. In prepared form, the plugsubstantially seals the first end of the chamber, thereby preventingloss of the drug formulation from the first end.

The device can be formed from any suitable material that is physicallyand/or chemically compatible with both the active drug and the liquiddiluent to be mixed therein. In certain embodiments, representativematerials for forming devices including the drug formulation chamber,the elongated tubular member, the end caps and tabs, include, withoutlimitation, paper, plastic such as propylene/styrene copolymers,polyproylene, high density polyethylene, low density polyethylene andthe like. The devices can have an inner diameter of between 3 mm and 8mm and a wall thickness of between 0.1 mm and 0.4 mm. The devices can bebetween 10 cm and 30 cm in length.

The fluid passing drug formulation retainer permits the free flow ofliquid medium but prohibits passage of the drug formulation from thedevice prior to delivery. Where the retainer comprises a one-way plug orvalve, the plug or valve will seal the straw at atmospheric pressure.When suction is applied, fluid will be drawn around the plug and intothe drug formulation chamber. Further, the plug has a density of lessthan one so that it will ascend to the top as the drug formulation isdelivered into the oral cavity. When suction is no longer applied, theplug will remain in the highest position it reached during sipping. Theplug can be prepared from closed cell polyethylene foam such asETHAFOAM®. Other forms of one way plugs can be a balloon of elastomericmaterial, a one-way mechanical ball valve and the like.

Examples of fluid that can be used for suspending the drug formulationby sipping through the drug formulation chamber include any palatableliquid such as water, juice, milk, soda, coffee, tea etc. Care must betaken to ensure compatibility of the fluid with the drug formulation.

In at least one embodiment, a dose sipping delivery device according tothe present invention can be prepared as follows. Jumbo size straws withan inside diameter of 0.21 inches and a length of 8 inches are heatsealed at one end. The seal is partially cut off so that the “one-way”plug cannot escape. The partially sealed end is enclosed by half of asize 1 hard gelatin capsule. Microparticles are then placed inside theopen end of the straw. A “one-way” plug made of closed cell polyethylenefoam, MICROFOAM® (DuPont) is trimmed to snugly fit inside the straw. Theplug is then placed inside the straw, on top of the microparticles.During operation, the plug end of the straw is placed into a glass ofwater and the protective gelatin capsule on the top of the straw isremoved. By slowly applying suction through the partially sealed end ofthe straw, the microparticles are sucked into the mouth and easilyswallowed.

Osmotic Dosage Forms

Osmotic dosage forms, osmotic delivery devices, modified release osmoticdosage forms, or osmosis-controlled extended-release systems are termsused interchangeably herein and are defined to mean dosage forms whichforcibly dispense the bupropion salt by pressure created by osmosis orby osmosis and diffusion of fluid into a material which expands andforces the bupropion salt to be dispensed from the osmotic dosage form.Osmosis can be defined as the flow of solvent from a compartment with alow concentration of solute to a compartment with a high concentrationof solute. The two compartments are separated by a membrane, wall, orcoat, which allows flow of solvent (a liquid, aqueous media, orbiological fluids) but not the solute. Examples of such membranes canfor example be, a semipermeable membrane, microporous, asymmetricmembrane, which asymmetric membrane can be permeable, semipermeable,perforated, or unperforated and can deliver the bupropion salt byosmotic pumping, diffusion or the combined mechanisms of diffusion andosmotic pumping. Thus, in principle, osmosis controlled release of thebupropion salt involves osmotic transport of an aqueous media into theosmotic dosage form followed by dissolution of the bupropion salt andthe subsequent transport of the saturated solution of the bupropion saltby osmotic pumping of the solution through at least one passageway inthe semipermeable membrane or by a combination of osmosis and diffusionthrough the semipermeable membrane.

It is well known to one of ordinary skill in the art that the desiredin-vitro release rate and the in-vivo pharmacokinetic parameters can beinfluenced by several factors, such as for example, the amount of thebupropion salt used to form the core, the amount of pharmaceuticallyacceptable excipient used to form the core, the type of pharmaceuticallyacceptable excipient used to form the core, the amount or type of anyother materials used to form the core such as, for example, osmagents(the term osmagent, osmotically effective solutes, osmotically effectivecompound and osmotic agents are used interchangeably herein)osmopolymers, and any combination thereof. The release profile can alsobe influenced by the material used to form the semipermeable membranecovering the core or by the material used to form any coating, such as acontrol-releasing coating (e.g. a release slowing-coat) on thesemipermeable membrane. With these factors in mind, an osmotic devicecan therefore be designed to exhibit an in-vitro release rate such thatin certain embodiments, after 2 hours from 0 to 20% by weight of thebupropion salt is released, after 4 hours from 15% to 45% by weight ofthe bupropion salt is released, after 8 hours, from 40% to 90% by weightof the bupropion salt is released, and after 16 hours, more than 80% byweight of the bupropion salt is released, when measured for example byusing a USP Type I apparatus (Rotating Basket Method) in 900 ml water,0.1N HCl, 0.1N HCl+0.1% Cetrimide, USP Buffer pH 1.5, Acetate Buffer pH4.5, Phosphate Buffer, pH 6.5 or Phosphate Buffer pH 7.4 at 75 rpm at37° C.±0.5° C. Alternatively dissolution may be effected in USP-3 mediasuch as SGF pH 1.2, Acetate Buffer at pH 4.5 or phosphate buffer at pH6.8.

Osmotic devices also may be designed to achieve an in vitro release ofno more than 40% after 2 hours, 40-75% release after 4 hours, at least75% after 8 hours, and at least 85% after 16 hours when assayed using adissolution medium such as identified above or known in the art.

In certain embodiments of the present invention, an osmotic dosage formis provided having a core comprising the bupropion salt and one or moreexcipients. In at least one embodiment the osmotic dosage form comprisesan osmagent. The osmotic delivery system for example, can be in the formof a tablet or capsule containing microparticles.

In certain embodiments, the core of the osmotic dosage form comprises awater swellable polymer, non-limiting examples of which includehydroxypropyl cellulose, alkylcellulose, hydroxyalkylcellulose,polyalkylene oxide, polyethylene oxide, and mixtures thereof. A bindercan be included in the core of certain embodiments of the osmotic dosageform to increase the core's mechanical strength. Non-limiting examplesof binders include polyvinyl pyrollidine, carboxyvinyl polymer,methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose,hydroxypropylmethylcellulose, a low molecular weight polyethylene oxidepolymer, hydroxypropylmethylcellulose, dextrin, maltodextrin, gelatin,polyvinyl alcohol, xanthan gum, carbomers, caragheen, starchderivatives, and mixtures thereof. Lubricants can be included in certainembodiments of the osmotic dosage form to provide decreased frictionbetween the solid and die wall during tablet manufacturing. Non-limitingexamples of lubricants include stearic acid, magnesium stearate,glyceryl behenate, talc, mineral oil, sodium stearyl fumarate,hydrogenated vegetable oil, sodium benzoate, calcium stearate, andmixtures thereof. In other embodiments, additional inert excipientsconsistent with the objects of the invention can also be included in thecore of the osmotic dosage form to facilitate the preparation and/orimprove patient acceptability of the final osmotic dosage form asdescribed herein. Suitable inert excipients are well known to theskilled artisan and can be found in the relevant literature, for examplein the Handbook of Pharmaceutical Excipients (Rowe et. al., 4th Ed.,Pharmaceutical Press, 2003).

In at least one embodiment, the present invention comprises a modifiedrelease osmotic dosage form comprising bupropion hydrobromide present ina therapeutically effective amount which releases the bupropionhydrobromide by forcibly dispensing the bupropion hydrobromide from acore via a semipermeable membrane by diffusion and/or at least onepassageway in the membrane by osmotic pumping (i) all or in part bypressure created in the core by osmosis i.e., positive hydrostaticpressure of a liquid, solvent, biological fluid or aqueous media and/orall or in part by the expansion of a swellable material which forces thebupropion hydrobromide to be dispensed from the core of the dosage form,and (ii) is formulated such that the dosage form exhibits an in-vitrorelease rate such that after 2 hours from 0 to 20% by weight of thebupropion salt is released, after 4 hours from 15% to 45% by weight ofthe bupropion salt is released, after 8 hours, from 40% to 90% by weightof the bupropion salt is released, and after 16 hours, more than 80% byweight of the bupropion salt is released.

In at least one embodiment, the modified release dosage form comprisesan osmotic delivery device comprising a homogenous solid core comprisingsubstantially the bupropion salt present in a therapeutically effectiveamount with at least one pharmaceutically acceptable excipient, saidcore surrounded by a semipermeable membrane which permits entry of anaqueous liquid into the core and delivery of the bupropion salt from thecore to the exterior of the dosage form through at least one passagewayor by a combination of osmosis and diffusion such that the dosage formexhibits an in-vitro release rate such that after 2 hours from 0 to 20%by weight of the bupropion salt is released, after 4 hours from 15% to45% by weight of the bupropion salt is released, after 8 hours, from 40%to 90% by weight of the bupropion salt is released, and after 16 hours,more than 80% by weight of the bupropion salt is released, or after 2hours no more than 40% is released, after 4 hours 40-75% is released,after 8 hours at least 75% is released and after 16 hours at least 85%is released.

In at least one embodiment, the modified release dosage form comprises amultiparticulate dosage form, each microparticle comprising an osmoticdelivery device, each microparticle comprising a homogenous solid corecomprising substantially the bupropion salt with at least onepharmaceutically acceptable excipient, said core of each microparticlesurrounded by a semipermeable membrane which permits entry of an aqueousliquid into the core and delivery of the bupropion salt from the core tothe exterior of the dosage form through a plurality of pores formed inthe semipermeable membrane by inclusion of a pore forming agent in themembrane or by a combination of osmosis and diffusion so as to allowcommunication of the core with the outside of the device for delivery ofthe bupropion salt and is formulated such that the dosage form comprisesa therapeutically effective amount of the bupropion salt and exhibits anin-vitro release rate such that after 2 hours from 0 to 20% by weight ofthe bupropion salt is released, after 4 hours from 15% to 45% by weightof the bupropion salt is released, after 8 hours, from 40% to 90% byweight of the bupropion salt is released, and after 16 hours, more than80% by weight of the bupropion salt is released or after 2 hours no morethan 40% is released, after 4 hours from 40-75% is released, after 8hours at least 75% is released and after 16 hours at least 85% isreleased.

In at least one embodiment, the modified release dosage form comprises amultiparticulate dosage form, each microparticle comprising an osmoticdelivery device, each microparticle comprising a homogenous solid corecomprising substantially the bupropion salt in admixture with at leastone pharmaceutically acceptable excipient, an osmagent and/or anosmopolymer, said core of each microparticle surrounded by asemipermeable membrane which permits entry of an aqueous liquid into thecore and delivery of the bupropion salt from the core to the exterior ofthe dosage form through a plurality of pores formed in the semipermeablemembrane by inclusion of a pore forming agent in the membrane or by acombination of osmosis and by diffusion so as to allow communication ofthe core with the outside of the device for delivery of the bupropionsalt and is formulated such that the dosage form comprises atherapeutically effective amount of the bupropion salt and exhibits anin-vitro release rate such that after 2 hours from 0 to 20% by weight ofthe bupropion salt is released, after 4 hours from 15% to 45% by weightof the bupropion salt is released, after 8 hours, from 40% to 90% byweight of the bupropion salt is released, and after 16 hours, more than80% by weight of the bupropion salt is released or after 2 hours no morethan 40% is released, after 4 hours from 40-75% is released, after 8hours at least 75% is released and after 16 hours at least 85% isreleased.

In at least one embodiment, the modified release dosage form comprises amultiparticulate dosage form, each microparticle comprising a homogenoussolid core comprising substantially the bupropion salt with at least onepharmaceutically acceptable excipient in admixture with an osmagent,and/or an osmopolymer, and/or an absorption enhancer, saidmicroparticles compressed into a tablet together with at least onepharmaceutically acceptable excipient, said tablet surrounded by asemipermeable membrane which permits entry of an aqueous liquid into thecore and delivery of the bupropion salt from the tablet interior to theexterior of the dosage form through at least one passageway in thesemipermeable membrane and/or by diffusion through the semipermeablemembrane so as to allow communication of the tablet interior with theexterior of the tablet for delivery of the bupropion salt and isformulated such that the dosage form comprises a therapeuticallyeffective amount of the bupropion salt and exhibits an in-vitro releaserate such that after 2 hours from 0 to 20% by weight of the bupropionsalt is released, after 4 hours from 15% to 45% by weight of thebupropion salt is released, after 8 hours, from 40% to 90% by weight ofthe bupropion salt is released, and after 16 hours, more than 80% byweight of the bupropion salt is released or after 2 hours no more than40% is released, after 4 hours from 40-75% is released, after 8 hours atleast 75% is released and after 16 hours at least 85% is released.

In at least one embodiment, the modified release dosage form comprises amultiparticulate dosage form, each microparticle comprising a sugarsphere or nonpareil bead coated with at least one layer comprisingsubstantially the bupropion salt with at least one pharmaceuticallyacceptable excipient, said at least one layer surrounded by asemipermeable membrane which permits entry of an aqueous liquid into thelayer and delivery of the bupropion salt from the layer to the exteriorof the dosage form through a plurality of pores formed in thesemipermeable membrane by inclusion of a pore forming agent in themembrane and/or by diffusion so as to allow communication of the corewith the outside of the device for delivery of the bupropion salt and isformulated such that the dosage form comprises a therapeuticallyeffective amount of the bupropion salt and exhibits an in-vitro releaserate such that after 2 hours from 0 to 20% by weight of the bupropionsalt is released, after 4 hours from 15% to 45% by weight of thebupropion salt is released, after 8 hours, from 40% to 90% by weight ofthe bupropion salt is released, and after 16 hours, more than 80% byweight of the bupropion salt is released or after 2 hours no more than40% is released, after 4 hours from 40-75% is released, after 8 hours atleast 75% is released and after 16 hours at least 85% is released.

In at least one embodiment, the modified release dosage form comprises amultiparticulate dosage form, each microparticle comprising a sugarsphere or nonpareil bead coated with at least one layer comprisingsubstantially the bupropion salt in admixture with at least onepharmaceutically acceptable excipient, an osmagent and/or anosmopolymer, said at least one layer surrounded by a semipermeablemembrane which permits entry of an aqueous liquid into the layer anddelivery of the bupropion salt from the layer to the exterior of thedosage form through a plurality of pores formed in the semipermeablemembrane by inclusion of a pore forming agent in the membrane and/or bydiffusion so as to allow communication of the core with the outside ofthe device for delivery of the bupropion salt and is formulated suchthat the dosage form comprises a therapeutically effectivc amount of thebupropion salt and exhibits an in-vitro release rate such that after 2hours from 0 to 20% by weight of the bupropion salt is released, after 4hours from 15% to 45% by weight of the bupropion salt is released, after8 hours, from 40% to 90% by weight of the bupropion salt is released,and after 16 hours, more than 80% by weight of the bupropion salt isreleased, or after 2 hours no more than 40% is released, after 4 hoursfrom 40-75% is released, after 8 hours at least 75% is released andafter 16 hours at least 85% is released.

In at least one embodiment, the modified release dosage form comprises amodified release osmotic dosage form comprising a homogenous corecomprising a therapeutically effective amount of the bupropion salt inadmixture with an osmagent, and/or an osmopolymer, and/or and absorptionenhancer, said core surrounded by a nontoxic wall, membrane or coat,such as for example a semipermeable membrane which permits entry of anaqueous liquid into the core and delivery of the bupropion salt from thecore to the exterior of the dosage form through at least one passagewayin the semipermeable membrane and/or by diffusion through the membraneso as to allow communication of the core with the outside of the dosageform for delivery of the bupropion salt and is formulated such that thedosage form exhibits an in-vitro release rate such that after 2 hoursfrom 0 to 20% by weight of the bupropion salt is released, after 4 hoursfrom 15% to 45% by weight of the bupropion salt is released, after 8hours, from 40% to 90% by weight of the bupropion salt is released, andafter 16 hours, more than 80% by weight of the bupropion salt isreleased or after 2 hours no more than 40% is released, after 4 hoursfrom 40-75% is released, after 8 hours at least 75% is released andafter 16 hours at least 85% is released.

In at least one embodiment the modified release dosage form comprises anosmotic delivery device comprising the bupropion salt present in atherapeutically effective amount in a layered, contacting arrangementwith a swellable material composition to yield a solid core with two ormore layers, which core is surrounded by a nontoxic wall, membrane orcoat, such as for example a semipermeable membrane which permits entryof an aqueous liquid into the core and delivery of the bupropion saltfrom the core to the exterior of the dosagc form through at least onepassageway in the semipermeable membrane or by osmosis and diffusionthrough the membrane so as to allow communication of the core with theoutside of the dosage form for delivery of the bupropion salt and isformulated such that the dosage form exhibits an in-vitro release ratesuch that after 2 hours from 0 to 20% by weight of the bupropion salt isreleased, after 4 hours from 15% to 45% by weight of the bupropion saltis released, after 8 hours, from 40% to 90% by weight of the bupropionsalt is released, and after 16 hours, more than 80% by weight of thebupropion salt is released; or a device wherein after 2 hours no morethan 40% is released, after 4 hours 40-75% is released, after 8 hours atleast 75% is released and after 16 hours at least 85% is released.

In at least one embodiment, the modified release dosage form comprisesan osmotic delivery device comprising a core and a membrane surroundingsaid core, said core comprising a therapeutically effective amount ofthe bupropion salt, and optionally at least one means for forciblydispensing the bupropion salt from the device, said membrane comprisingat least one means for the exit of the bupropion salt from the device,said device formulated such that when the device is in an aqueousmedium, the bupropion salt, and optionally the at least one means forforcibly dispensing the bupropion salt from the device and the at leastone means for the exit of the bupropion salt from the devicecooperatively function to exhibit an in-vitro release rate such thatafter 2 hours from 0 to 20% by weight of the bupropion salt is released,after 4 hours from 15% to 45% by weight of the bupropion salt isreleased, after 8 hours, from 40% to 90% by weight of the bupropion saltis released, and after 16 hours, more than 80% by weight of thebupropion salt is released; or a device wherein after 2 hours no morethan 40% is released, after 4 hours from 40-75% is released, after 8hours at least 75% is released and after 16 hours at least 85% isreleased.

In at least one embodiment, the modified release dosage form comprisesan osmotic delivery device comprising a core and a membrane surroundingsaid core, said core comprising a therapeutically effective amount ofthe bupropion salt, at least one means for increasing the hydrostaticpressure inside the membrane and optionally at least one means forforcibly dispensing the bupropion salt from the device, said membranecomprising at least one means for the exit of the bupropion salt fromthe device, said device formulated such that when the device is in anaqueous medium, the at least one means for increasing the hydrostaticpressure inside the membrane, and optionally the at least one means forforcibly dispensing the bupropion salt from the device and the at leastone means for the exit of the bupropion salt cooperatively function toexhibit an in-vitro release rate such that after 2 hours from 0 to 20%by weight of the bupropion salt is released, after 4 hours from 15% to45% by weight of the bupropion salt is released, after 8 hours, from 40%to 90% by weight of the bupropion salt is released, and after 16 hours,more than 80% by weight of the bupropion salt is released; or a devicewherein after 2 hours no more than 40% is released, after 4 hours from40-75% is released, after 8 hours at least 75% is released and after 16hours at least 85% is released.

In at least one embodiment the invention is directed to once-a-daybupropion hydrobromide sustained release formulations that isbioequivalent according to FDA guidelines to WELLBUTRIN™ ER orZYBAN™/WELLBUTRIN™ SR when administered once-daily to a subject in needthereof and wherein the bupropion salt contained is more stable than thebupropion hydrochloride salt contained in Wellbutrin ER or Zyban whenstored at 40 degrees C. and 75% relative humidity for at least 3, 4 5and/or at least 6 months. Particularly, the invention encompassesbioequivalent 150 mg, 174 mg, 300 mg or 348 mg bupropion HBr containingformulations.

In at least one embodiment the invention is directed to topicalformulations containing bupropion hydrobromide that may be administeredtopically, e.g., transmucosally or transdermally. Particularly, theinvention embraces topically administrable gels and patch type deliverydevices which potentially may comprise another active agent such asnicotine.

In at least one embodiment the invention is directed to inhalablepulmonary deliverable compositions containing bupropion hydrobromidethat may be administered via pulmonary delivery to a subject in needthereof. Preferably, these compositions are produced according to theaerosol technology disclosed in U.S. Pat. Nos. 6,682,716; 6,716,415;6,716,417; 6,783,753; 7,029,658; and 7,033,575 and others assigned toAlexza Corporation. These patents in particular disclose the use of suchmethods in producing aerosols containing anti-depressants for pulmonarydelivery.

In at least one embodiment the invention is directed to injectablecompositions comprising an effective amount of bupropion hydrobromideand a pharmaceutically acceptable carrier or excipient.

In at least one embodiment, the invention is directed to a method oftreating a condition comprising administering any one of the abovedescribed osmotic dosage forms to a patient in need of suchadministration once-daily.

The invention, in at least one embodiment, is directed to a method foradministering a bupropion salt to the gastrointestinal tract of a humanfor the treatment or management of a condition, wherein the methodcomprises: (a) admitting orally into the human a modified release dosageform comprising a bupropion salt, the modified release dosage formcomprising an osmotic dosage form; and (b) administering the bupropionsalt from the osmotic dosage form in a therapeutically responsive doseto produce the treatment or management of the condition such that theosmotic dosage form exhibits an in-vitro release rate such that after 2hours from 0 to 20% by weight of the bupropion salt is released, after 4hours from 15% to 45% by weight of the bupropion salt is released, after8 hours, from 40% to 90% by weight of the bupropion salt is released,and after 16 hours, more than 80% by weight of the bupropion salt isreleased; or a dosage form wherein after 2 hours no more than 40% isreleased, after 4 hours from 40-75% is released, after 8 hours at least75% is released and after 16 hours at least 85% is released.

The invention, in at least one embodiment, is directed to a method foradministering a bupropion salt to the gastrointestinal tract of a humanfor the treatment or management of a condition, wherein the methodcomprises: (a) admitting orally into the human a modified release dosageform comprising a core and a membrane surrounding said core, said corecomprising the bupropion salt and optionally a means for forciblydispensing the bupropion salt from the device, said membrane comprisingat least one means for the exit of the bupropion salt from the dosageform, and (b) administering the bupropion salt from the dosage formwhich is formulated such that when the dosage form is in an aqueousmedium, the bupropion salt and optionally the means for forciblydispensing the bupropion salt and the at least one means for the exit ofthe bupropion salt cooperatively function to exhibit an in-vitro releaserate such that after 2 hours from 0 to 20% by weight of the bupropionsalt is released, after 4 hours from 15% to 45% by weight of thebupropion salt is released, after 8 hours, from 40% to 90% by weight ofthe bupropion salt is released, and after 16 hours, more than 80% byweight of the bupropion salt is released; or a medicament wherein after2 hours no more than 40% is released, after 4 hours from 40-75% isreleased, after 8 hours at least 75% is released and after 16 hours atleast 85% is released.

The invention, in at least one embodiment, is directed to a method foradministering a bupropion salt to the gastrointestinal tract of a humanfor the treatment or management of a condition, wherein the methodcomprises: (a) admitting orally into the human a modified release dosageform comprising a core and a membrane surrounding said core, said corecomprising the bupropion salt, a means for increasing the hydrostaticpressure within the core and optionally a means for forcibly dispensingthe bupropion salt from the device, said membrane comprising at leastone means for the exit of the bupropion salt from the dosage form, and(b) administering the bupropion salt from the dosage form which isformulated such that when the dosage form is in an aqueous medium, thebupropion salt, the means for increasing the hydrostatic pressure withinthe core and optionally the means for forcibly dispensing the bupropionsalt and the at least one means for the exit of the bupropion saltcooperatively function to exhibit an in-vitro release rate such thatafter 2 hours from 0 to 20% by weight of the bupropion salt is released,after 4 hours from 15% to 45% by weight of the bupropion salt isreleased, after 8 hours, from 40% to 90% by weight of the bupropion saltis released, and after 16 hours, more than 80% by weight of thebupropion salt is released, or a device wherein after 2 hours no morethan 40% is released, after 4 hours from 40-75% is released, after 8hours at least 75% is released and after 16 hours at least 85% isreleased.

In at least one other embodiment, the osmotic dosage form furthercomprises an immediate release coat for the immediate release of thebupropion salt from the immediate release coat. In embodimentscomprising the immediate release coat, the osmotic dosage form exhibitsan in-vitro release rate such that after 2 hours from 0 to 20% by weightof the bupropion salt is released, after 4 hours from 15% to 45% byweight of the bupropion salt is released, after 8 hours, from 40% to 90%by weight of the bupropion salt is released, and after 16 hours, morethan 80% by weight of the bupropion salt is released or a dosage formwherein after 2 hours no more than 40% is released, after 4 hours from40-75% is released, after 8 hours at least 75% is released or after 16hours at least 85% is released.

In at least one other embodiment, the osmotic dosage forms furthercomprise an inert water-soluble coat covering the semipermeable membraneor coat. This inert water-soluble coat can be impermeable in a firstexternal fluid, while being soluble in a second external fluid. Inembodiments comprising the inert water-soluble coat, the osmotic dosageform exhibits an in-vitro release rate such that after 2 hours from 0 to20% by weight of the bupropion salt is released, after 4 hours from 15%to 45% by weight of the bupropion salt is released, after 8 hours, from40% to 90% by weight of the bupropion salt is released, and after 16hours, more than 80% by weight of the bupropion salt is released or adosage form wherein after 2 hours no more than 40% is released, after 4hours from 40-75% is released, after 8 hours at least 75% is releasedand after 16 hours at least 85% is released.

In at least one other embodiment, the osmotic dosage forms furthercomprise an osmotic subcoat. In embodiments comprising the osmoticsubcoat, the osmotic dosage form exhibits an in-vitro release rate suchthat after 2 hours from 0 to 20% by weight of the bupropion salt isreleased, after 4 hours from 15% to 45% by weight of the bupropion saltis released, after 8 hours, from 40% to 90% by weight of the bupropionsalt is released, and after 16 hours, more than 80% by weight of thebupropion salt is released or a dosage form wherein after 2 hours nomore than 40% is released, after 4 hours from 40-75% is released, after8 hours at least 75% is released and after 16 hours at least 85% isreleased.

In at least one other embodiment, the osmotic dosage forms furthercomprise a control-releasing coat. The control-releasing coat of theosmotic dosage form can, for example, control, extend, and/or delay therelease of the bupropion salt. In embodiments comprising thecontrol-releasing coat, the osmotic dosage form exhibits an in-vitrorelease rate such that after 2 hours from 0 to 20% by weight of thebupropion salt is released, after 4 hours from 15% to 45% by weight ofthe bupropion salt is released, after 8 hours, from 40% to 90% by weightof the bupropion salt is released, and after 16 hours, more than 80% byweight of the bupropion salt is released or a dosage form wherein after2 hours no more than 40% is released, after 4 hours from 40-75% isreleased, after 8 hours at least 75% is released and after 16 hours atleast 85% is released.

In at least one other embodiment, the control-releasing coat of theosmotic dosage form comprises a material that is soluble or erodible inintestinal juices, substantially pH neutral or basic fluids of fluidshaving a pH higher than gastric fluid, but for the most part insolublein gastric juices or acidic fluids.

In at least one embodiment, the control-releasing coat of the osmoticdosage form comprises at least one water-insoluble water-permeablefilm-forming polymer and at least one water-soluble polymer.

In at least one embodiment, the control-releasing coat of the osmoticdosage form comprises at least one water-insoluble water-permeablefilm-forming polymer and at least one water-soluble polymer andoptionally at least one plasticizer.

In at least one embodiment, the control-releasing coat of the osmoticdosage form comprises at least one water-insoluble water-permeablefilm-forming polymer, at least one water-soluble polymer and at leastone means for the exit of the bupropion salt from the core of theosmotic dosage form.

In at least one embodiment, the control-releasing coat of the osmoticdosage form comprises at least one water-insoluble water-permeablefilm-forming polymer, at least one water-soluble polymer and at leastone passageway.

In at least one embodiment, the control-releasing coat of the osmoticdosage form comprises at least one water-insoluble water-permeablefilm-forming polymer, at least one water-soluble polymer and at leastone plasticizer.

In at least one embodiment, the control-releasing coat of the osmoticdosage form comprises at least one water-insoluble water-permeablefilm-forming polymer, at least one water-soluble polymer, optionally atleast one plasticizer, and at least one means for the exit of thebupropion salt from the core of the osmotic dosage form.

In at least one embodiment, the control-releasing coat of the osmoticdosage form comprises at least one water-insoluble water-permeablefilm-forming polymer, at least one water-soluble polymer, optionally atleast one plasticizer, and at least one passageway.

In at least one embodiment, the control-releasing coat of the osmoticdosage form comprises an aqueous dispersion of a neutral ester copolymerwithout any functional groups; a poly glycol having a melting pointgreater than 55° C., one or more pharmaceutically acceptable excipients,and optionally at least one means for the exit of the bupropion saltform the core of the osmotic dosage form. This control-releasing coat iscured at a temperature at least equal to or greater than the meltingpoint of the polyglycol.

In at least one other embodiment, the control-releasing coat of theosmotic dosage form comprises at least one enteric polymer.

The membrane or wall is permeable to the passage of aqueous media butnot to the passage of the bupropion salt present in the core. Themembrane can be, for example, a semipermeable membrane or an asymmetricmembrane, which can be permeable, semipermeable, perforated, orunperforated and can deliver the bupropion salt by osmotic pumping, orthe combined mechanisms of diffusion and osmotic pumping. The structuralintegrity of such membranes should remain substantially intact duringthe period of delivery of the bupropion salt. By “substantially intact”it is meant that the semipermeable property of the membrane is notcompromised during the period of delivery of the bupropion salt.

The semipermeable membrane of the osmotic dosage form comprises at leastone pharmaceutically acceptable excipient, at least one polymer, wax, orcombination thereof, although appropriately treated inorganic materialssuch as ceramics, metals or glasses can be used. When the semipermeablemembrane comprises at least one polymer, the molecular weight of the atleast one polymer or combination of polymers should be such that thepolymer or combination of polymers is solid at the temperature of usei.e., both in-vitro and in-vivo.

In certain embodiments, the at least one polymer included in thesemipermeable membrane of the osmotic dosage form can be a celluloseester, such as for example, cellulose acetate, cellulose acetateacetoacetate, cellulose acetate benzoate, cellulose acetatebutylsulfonate, cellulose acetate butyrate, cellulose acetate butyratesulfate, cellulose acetate butyrate valerate, cellulose acetate caprate,cellulose acetate caproate, cellulose acetate caprylate, celluloseacetate carboxymethoxypropionate, cellulose acetate chloroacetate,cellulose acetate dimethaminoacetate, cellulose acetatedimethylaminoacetate, cellulose acetate dimethylsulfamate, celluloseacetate dipalmitate, cellulose acetate dipropylsulfamate, celluloseacetate ethoxyacetate, cellulose acetate ethyl carbamate, celluloseacetate ethyl carbonate, cellulose acetate ethyl oxalate, celluloseacetate furoate, cellulose acetate heptanoate, cellulose acetateheptylate, cellulose acetate isobutyrate, cellulose acetate laurate,cellulose acetate methacrylate, cellulose acetate methoxyacetate,cellulose acetate methylcarbamate, cellulose acetate methylsulfonate,cellulose acetate myristate, cellulose acetate octanoate, celluloseacetate palmitate, cellulose acetate phthalate, cellulose acetatepropionate, cellulose acetate propionate sulfate, cellulose acetatepropionate valerate, cellulose acetate p-toluene sulfonate, celluloseacetate succinate, cellulose acetate sulfate, cellulose acetatetrimellitate, cellulose acetate tripropionate, cellulose acetatevalerate, cellulose benzoate, cellulose butyrate napthylate, cellulosebutyrate, cellulose chlorobenzoate, cellulose cyanoacetates, cellulosedicaprylate, cellulose dioctanoate, cellulose dipentanate, cellulosedipentanlate, cellulose formate, cellulose methacrylates, cellulosemethoxybenzoate, cellulose nitrate, cellulose nitrobenzoate, cellulosephosphate (sodium salt), cellulose phosphinates, cellulose phosphites,cellulose phosphonates, cellulose propionate, cellulose propionatecrotonate, cellulose propionate isobutyrate, cellulose propionatesuccinate, cellulose stearate, cellulose sulfate (sodium salt),cellulose triacetate, cellulose tricaprylate, cellulose triformate,cellulose triheptanoate, cellulose triheptylate, cellulose trilaurate,cellulose trimyristate, cellulose trinitrate, cellulose trioctanoate,cellulose tripalmitate, cellulose tripropionate, cellulose trisuccinate,cellulose trivalerate, cellulose valerate palmitate; a cellulose ether,such as for example, 2-cyanoethyl cellulose, 2-hydroxybutyl methylcellulose, 2-hydroxyethyl cellulose, 2-hydroxyethyl ethyl cellulose,2-hydroxyethyl methyl cellulose, 2-hydroxypropyl cellulose,2-hydroxypropyl methyl cellulose, dimethoxyethyl cellulose acetate,ethyl 2-hydroxylethyl cellulose, ethyl cellulose, ethyl cellulosesulfate, ethylcellulose dimethylsulfamate, methyl cellulose, methylcellulose acetate, methylcyanoethyl cellulose, sodium carboxymethyl2-hydroxyethyl cellulose, sodium carboxymethyl cellulose; a polysulfone,such as for example, polyethersulfones; a polycarbonate; a polyurethane;a polyvinyl acetate; a polyvinyl alcohol; a polyester; a polyalkene suchas polyethylene, ethylene vinyl alcohol copolymer, polypropylene,poly(1,2-dimethyl-1-butenylene), poly(1-bromo-1-butenylene), poly(1,butene), poly(1-chloro-1-butenylene), poly(1-decyl-1-butenylene),poly(1-hexane), poly(1-isopropyl-1-butenylene), poly(1-pentene),poly(3-vinylpyrene), poly(4-methoxyl 1-butenylene),poly(ethylene-co-methyl styrene), poly vinyl-chloride,poly(ethylene-co-tetrafluoroethylene), poly(ethylene-terephthalate),poly(dodecafluorobutoxylethylene), poly(hexafluoroprolylene),poly(hexyloxyethylene), poly(isobutene), poly(isobutene-co-isoprene),poly(isoprene), poly-butadiene, poly[(pentafluoroethyl)ethylene],poly[2-ethylhexyloxy)ethylene], poly(butylethylene),poly(tertbutylethylene), poly(cylclohexylethyl-lene),poly[(cyclohexylmethyl)ethylene], poly(cyclopentylethylene),poly(decylethylene), poly-(dodecy-lethylene), poly(neopentylethylene),poly(propylethylene); a polystyrene, such as for example,poly(2,4-dimethyl styrene), poly(3-methyl styrene),poly(4-methoxystyrene), poly(4-methoxystyrene-stat-styrene),poly(4-methyl styrene), poly(isopentyl styrene), poly(isopropylstyrene), polyvinyl esters or polyvinyl ethers, such as form example,poly(benzoylethylene), poly(butoxyethylene), poly(chloroprene),poly(cyclohexloxyethylene), poly(decyloxyethylene),poly(dichloroethylene), poly(difluoroethylene), poly(vinyl acetate),poly(vinyltrimethyllstyrene); a polysiloxane, such as for example,poly(dimethylsiloxane); a polyacrylic acid derivative, such as forexample, polyacrylates, polymethyl methacrylate, poly(acrylic acid)higher alkyl esters, poly(ethylmethacrylate), poly(hexadecylmethacrylate-co-methylmethacrylate), poly-(methylacrylate-co-styrene),poly(n-butyl methacrylate), poly(n-butyl-acrylate), poly (cyclododecylacrylate), poly(benzyl acrylate), poly(butylacrylate),poly(secbutylacrylate), poly(hexyl acrylate), poly(octyl acrylate),poly(decyl acrylate), poly(dodecyl acrylate), poly(2-methyl butylacrylate), poly(adamantyl methacrylate), poly(benzyl methacrylate),poly(butyl methacrylate), poly(2-ethylhexyl methacrylate), poly(octylmethacrylate), acrylic resins; a polyamide, such as for example,poly(iminoadipoyliminododecamethylene),poly(iminoadipoyliminohexamethylene), polyethers, such as for example,poly(octyloxyethylene), poly(oxyphenylethylene), poly(oxypropylene),poly(pentyloxyethylene), poly(phenoxy styrene),poly(secbutroxylethylene), poly(tert-butoxyethylene); and combinationsthereof.

In at least one embodiment, the at least one wax included in thesemipermeable membrane of the osmotic dosage form can be, for example,insect and animal waxes, such as for example, chinese insect wax,beeswax, spermaceti, fats and wool wax; vegetable waxes, such as forexample, bamboo leaf wax, candelilla wax, carnauba wax, Japan wax,ouricury wax, Jojoba wax, bayberry wax, Douglas-Fir wax, cotton wax,cranberry wax, cape berry wax, rice-bran wax, castor wax, indian cornwax, hydrogenated vegetable oils (e.g., castor, palm, cottonseed,soybean), sorghum grain wax, Spanish moss wax, sugarcane wax, carandawax, bleached wax, Esparto wax, flax wax, Madagascar wax, orange peelwax, shellac wax, sisal hemp wax and rice wax; mineral waxes, such asfor example, Montan wax, peat waxes, petroleum wax, petroleum ceresin,ozokerite wax, microcrystalline wax and paraffins; synthetic waxes, suchas for example, polyethylene wax, Fischer-Tropsch wax, chemicallymodified hydrocarbon waxes, cetyl esters wax; and combinations thereof.

In at least one embodiment, the semipermeable membrane of the osmoticdosage form can comprise a combination of at least one polymer, wax, orcombinations thereof and optionally at least one excipient. The totalweight percent of all components comprising the semipermeable membraneis 100%.

In embodiments where the bupropion salt is released through the membraneor wall in a controlled manner by the combined mechanisms of diffusionand osmotic pumping, the membrane or wall can comprise at least one ofthe above described polymers and/or waxes or a combination of polymers,such as for example, cellulose esters, copolymers of methacrylate saltsand optionally a plasticizer.

The poly(methacrylate) copolymer salts used in the manufacturing of themembrane for the osmotic dosage form can be, for example, insoluble inwater and in digestive fluids, but are permeable to different degrees.Examples of such copolymers are poly(ammonium methacrylate) copolymer RL(EUDRAGIT® RL), poly(ammonium methacrylate) copolymer (type A-USP/NF),poly(aminoalkyl methacrylate) copolymer RL-JSP I), and (ethylacrylate)-(methylmethacrylate)-[(trimethylammonium)-ethacrylate](1:2:0.2) copolymer, MW150,000. Other examples of such copolymers include those available fromRohm Pharma, Weiterstadt, such as for example, EUDRAGIT® RS100: solidpolymer, EUDRAGIT® RL 12.5:12.5% solution in solvent, EUDRAGIT® RL 30D:30% aqueous dispersion, and other equivalent products. The followingpoly (ammonium methacrylate) copolymers can also be used: ammoniummethacrylate copolymer RS (EUDRAGIT®RS), poly(ammonium methacrylate)copolymer (type B-USP/NF), poly(aminoalkyl methacrylate) copolymer(RSL-JSP I), (ethyl acrylate)-(methylmethacrylate)-[(trimethylammonium)-ethyl methacrylate](1:2:0.1)copolymer, PM 150,000. Specific polymers include (Rohm Pharma,Weiterstadt): EUDRAGIT®RS100: solid polymer, EUDRAGIT®RS12.5: 12.5%solution in solvent, EUDRAGIT®RS 30D: 30% aqueous dispersion and otherequivalent products. RL is readily water permeable while EUDRAGIT®RS ishardly water permeable. By employing mixtures of both EUDRAGIT®RL andEUDRAGIT®RS, membranes having the desired degree of permeability toachieve the in-vitro dissolution rates and in-vivo pharmacokineticparameters can be prepared.

The use of plasticizers is optional but can be included in the osmoticdosage forms to modify the properties and characteristics of thepolymers used in the coats or core of the osmotic dosage forms forconvenient processing during manufacture of the coats and/or the core ofthe osmotic dosage forms if necessary. As used herein, the term“plasticizer” includes any compounds capable of plasticizing orsoftening a polymer or binder used in invention. Once the coat ormembrane has been manufactured, certain plasticizers can function toincrease the hydrophilicity of the coat(s) and/or the core of theosmotic dosage form in the environment of use. During manufacture of thecoat, the plasticizer should be able to lower the melting temperature orglass transition temperature (softening point temperature) of thepolymer or binder. Plasticizers, such as low molecular weight PEG,generally broaden the average molecular weight of a polymer in whichthey are included thereby lowering its glass transition temperature orsoftening point. Plasticizers also can reduce the viscosity of apolymer. The plasticizer can impart some particularly advantageousphysical properties to the osmotic device of the invention.

Plasticizers useful in the osmotic dosage form of the invention caninclude, for example, low molecular weight polymers, oligomers,copolymers, oils, small organic molecules, low molecular weight polyolshaving aliphatic hydroxyls, ester-type plasticizers, glycol ethers,poly(propylene glycol), multi-block polymers, single block polymers, lowmolecular weight poly(ethylene glycol), citrate ester-type plasticizers,triacetin, propylene glycol, glycerin, ethylene glycol, 1,2-butyleneglycol, 2,3-butylene glycol, styrene glycol, diethylene glycol,triethylene glycol, tetraethylene glycol and other poly(ethylene glycol)compounds, monopropylene glycol monoisopropyl ether, propylene glycolmonoethyl ether, ethylene glycol monoethyl ether, diethylene glycolmonoethyl ether, sorbitol lactate, ethyl lactate, butyl lactate, ethylglycolate, dibutylsebacate, acetyltributylcitrate, triethyl citrate,acetyl triethyl citrate, tributyl citrate and allyl glycolate. All suchplasticizers are commercially available from sources such as Aldrich orSigma Chemical Co. It is also contemplated and within the scope of theinvention, that a combination of plasticizers can be used in the presentformulation. The PEG based plasticizers are available commercially orcan be made by a variety of methods, such as disclosed in Poly(ethyleneglycol) Chemistry: Biotechnical and Biomedical Applications (J. M.Harris, Ed.; Plenum Press, NY). Once the osmotic dosage form ismanufactured, certain plasticizers can function to increase thehydrophilicity of the coat(s) and/or the core of the osmotic dosage formin the environment of use may it be in-vitro or in-vivo. Accordingly,certain plasticizers can function as flux enhancers.

The ratio of cellulose esters:copolymers of methacrylatesalts:plasticizer of the osmotic dosage forms can be, for example, from1-99% of the cellulose ester by weight:84-0.5% of the copolymers ofmethacrylate salt by weight:15-0.5% of the plasticizer by weight. Thetotal weight percent of all components comprising the wall is 100%.

Aside from the semipermeable membranes of the osmotic dosage formdescribed above, asymmetric membranes can also be used to surround thecore of an osmotic dosage form for the controlled release of thebupropion salt to provide the in-vitro release rates described above andthe therapeutically beneficial in-vivo pharmacokinetic parameters forthe treatment or management of a condition. Such asymmetric membranescan be permeable, semipermeable, perforated, or unperforated and candeliver the bupropion salt by osmotic pumping, diffusion or the combinedmechanisms of diffusion and osmotic pumping. The reader is referred toU.S. Pat. No. 5,612,059 for the manufacture and use thereof ofasymmetric membranes for the controlled-release of an active through oneor more asymmetric membranes by osmosis or by a combination of diffusionosmotic pumping.

In certain embodiments of the osmotic dosage form, the semipermeablemembrane can further comprise a flux enhancing, or channeling agent.

“Flux enhancing agents” or “channeling agents” are any materials whichfunction to increase the volume of fluid imbibed into the core to enablethe osmotic dosage form to dispense substantially all of the bupropionsalt through at least one passageway in the semipermeable membrane byosmosis or by osmosis and by diffusion through the semipermeablemembrane. The flux enhancing agent dissolves to form paths in thesemipermeable membrane for the fluid to enter the core and dissolve thebupropion salt in the core together with the osmagent, if one ispresent, but does not allow exist of the bupropion salt. The fluxenhancing agent can be any water soluble material or an enteric materialwhich allows an increase in the volume of liquid imbibed into the corebut does not allow for the exit of the bupropion salt. Such materialscan be, for example, sodium chloride, potassium chloride, sucrose,sorbitol, mannitol, polyethylene glycol, propylene glycol, hydroxypropylcellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulosephthalate, cellulose acetate phthalate, polyvinyl alcohols, methacryliccopolymers, and combinations thereof. Some plasticizers can alsofunction as flux enhancers by increasing the hydrophilicity of thesemipermeable membrane and/or the core of the osmotic dosage form. Fluxenhancers or channeling agents can also function as a means for the exitof the bupropion salt from the core if the flux enhancing or channelingagent is used in a sufficient amount.

The expression “passageway” as used herein comprises means and methodssuitable for the metered release of the bupropion salt from the core ofthe osmotic dosage form. The means for the exit of the bupropion saltcomprises at least one passageway, including orifice, bore, aperture,pore, porous element, hollow fiber, capillary tube, porous overlay, orporous element that provides for the osmotic controlled release of thebupropion salt. The means for the exit can be linear or tortuous. Themeans for the exit includes a weakened area of the semipermeablemembrane or a material that erodes or is leached from the wall in afluid environment of use to produce at least one dimensioned passageway.The means for the exit of the bupropion salt can comprise any leachablematerial, which when leaches out of the semipermeable membrane forms apassageway suitable for the exit of the bupropion salt from the core ofthe osmotic dosage form. Such leachable materials can comprise, forexample, a leachable poly(glycolic) acid or poly(lactic) acid polymer inthe semipermeable membrane, a gelatinous filament, poly(vinyl alcohol),leachable polysaccharides, salts, oxides, sorbitol, or sucrose. Themeans for exit can also comprise a flux enhancer or channeling agent ifpresent in a sufficient amount. The means for the exit possessescontrolled-release dimensions, such as round, triangular, square andelliptical, for the metered release of the bupropion salt from thedosage form. The dimensions of the means of the exit for the bupropionsalt is sized such so as to allow the bupropion salt to pass through themeans for the exit. The dosage form can be constructed with one or moremeans for the exit in spaced apart relationship on a single surface oron more than one surface of the wall.

The expression “fluid environment” denotes an aqueous or biologicalfluid as in a human patient, including the gastrointestinal tract. Themeans for the exit can be preformed e.g., by mechanical means after thesemipermeable membrane is applied to the core of the osmotic dosageform, such as for example by mechanical perforation, laser perforation,or by using a properly sized projection on the interior of a tabletpunch to form the means for the exit of the bupropion salt, such as forexample a cylindrical or frustoconical pin which is integral with theinside surface of the upper punch of a punch used to form the osmoticdosage form. Alternatively, the means for the exit of the bupropion saltcan be formed by incorporating a leachable material or pore formingagent into the semipermeable composition before the semipermeablemembrane is applied to the core of the osmotic dosage form. The meansfor the exit of the bupropion salt can comprise a combination of thedifferent exit means described above. The osmotic dosage form cancomprise more than one means for the exit of the bupropion saltincluding two, three, four, five, six seven, eight, nine ten or moreexit means and can be formed in any place of the osmotic dosage form.The various positions of the means for the exit are disclosed, forexample, in U.S. Pat. No. 6,491,949. The type, number, and dimension(s)of the means for the exit of the bupropion salt is such that the dosageform exhibits the desired in-vitro release rates described herein andcan be determined by routine experimentation by those skilled in thepharmaceutical delivery arts. The means for the exit and equipment forforming the means for the exit are disclosed for example in U.S. Pat.Nos. 3,845,770; 3,916,899; 4,034,758; 4,063,064; 4,077,407, 4,088,864;4,200,098; 4,285,987; 4,783,337; 4,816,263; and 5,071,607.

The osmotic device can further comprise a control-releasing coatsurrounding the semipermeable membrane comprising an enteric or delayedrelease coat that is soluble or erodible in intestinal juices,substantially pH neutral or basic fluids of fluids having a pH higherthan gastric fluid, but for the most part insoluble in gastric juices oracidic fluids. A wide variety of other polymeric materials are known topossess these various solubility properties. Such other polymericmaterials include, for example, cellulose acetate phthalate (CAP),cellulose acetate trimelletate (CAT), poly(vinyl acetate) phthalate(PVAP), hydroxypropyl methylcellulose phthalate (HP), poly(methacrylateethylacrylate) (1:1) copolymer (MA-EA), poly(methacrylatemethylmethacrylate) (1:1) copolymer (MA-MMA), poly(methacrylatemethylmethacrylate) (1:2) copolymer, EUDRAGIT® L-30-D (MA-EA, 1:1),EUDRAGIT® L-100-55 (MA-EA, 1:1), hyciroxypropyl methylcellulose acetatesuccinate (HPMCAS), COATERIC® (PVAP), AQUATERIC® (CAP), AQUACOAT®(HPMCAS) and combinations thereof. The enteric coat can also comprisedissolution aids, stability modifiers, and bioabsorption enhancers.

When the control-releasing coat of osmotic dosage forms of the presentinvention is intended to be dissolved, eroded or become detached fromthe osmotic dosage form, materials such as hydroxypropylcellulose,microcrystalline cellulose (MCC, AVICEL™ from FMC Corp.), poly(ethylene-vinyl acetate) (60:40) copolymer (EVAC from Aldrich ChemicalCo.), 2-hydroxyethylmethacrylate (HEMA), MMA, terpolymers of H EMA:MMA:MA synthesized in the presence ofN,N′-bis(methacryloyloxyethyloxycarbonylamino)-azobenzene, azopolymers,enteric coated timed release system (TIME CLOCK® from PharmaceuticalProfiles, Ltd., UK) and calcium pectinate can be used.

Polymers for use in the control-releasing coat of osmotic dosage formsof the present invention can be, for example, enteric materials thatresist the action of gastric fluid avoiding permeation through thesemipermeable wall while one or more of the materials in the core of thedosage form are solubilized in the intestinal tract thereby allowingdelivery of the bupropion salt in the core by osmotic pumping in theosmotic dosage form to begin. A material that adapts to this kind ofrequirement can be, for example, a poly(vinylpyrrolidone)-vinyl acetatecopolymer, such as the material supplied by BASF under its KOLLIDON®VA64 trademark, mixed with magnesium stearate and other similarexcipients. The enteric coat can also comprise povidone, which issupplied by BASF under its KOLLIDON® K 30 trademark, and hydroxypropylmethylcellulose, which is supplied by Dow under its METHOCEL® E-15trademark. The materials can be prepared in solutions having differentconcentrations of polymer according to the desired solution viscosity.For example, a 10% P/V aqueous solution of KOLLIDON® K 30 has aviscosity of 5.5-8.5 cps at 20° C., and a 2% P/V aqueous solution ofMETHOCEL® E-15 has a viscosity of 13-18 cps at 20° C.

The control-releasing coat of osmotic dosage forms of the presentinvention can comprise one or more materials that do not dissolve,disintegrate, or change their structural integrity in the stomach andduring the period of time that the tablet resides in the stomach, suchas for example a member chosen from the group (a) keratin, keratinsaridarac-tolu, salol (phenyl salicylate), salol beta-naphthylbenzoateand acetotannin, salol with balsam of Peru, salol with tolu, salol withgum mastic, salol and stearic acid, and salol and shellac; (b) a memberchosen from the group of formalized protein, formalized gelatin, andformalized cross-linked gelatin and exchange resins; (c) a member chosenfrom the group of myristic acid-hydrogenated castor oil-cholesterol,stearic acid-mutton tallow, stearic acid-balsam of tolu, and stearicacid-castor oil; (d) a member chosen from the group of shellac,ammoniated shellac, ammoniated shellac-salol, shellac-wool fat,shellac-acetyl alcohol, shellac-stearic acid-balsam of tolu, and shellacn-butyl stearate; (e) a member chosen from the group of abietic acid,methyl abictate, benzoin, balsam of tolu, sandarac, mastic with tolu,and mastic with tolu, and mastic with acetyl alcohol; (f) acrylic resinsrepresented by anionic polymers synthesized from methacrylate acid andmethacrylic acid methyl ester, copolymeric acrylic resins of methacrylicand methacrylic acid and methacrylic acid alkyl esters, copolymers ofalkacrylic acid and alkacrylic acid alkyl esters, acrylic resins such asdimethylaminoethylmethacrylate-butylmethacrylate-methylmethacrylatecopolymer of 150,000 molecular weight, methacrylicacid-methylmethacrylate 50:50 copolymer of 135,000 molecular weight,methacrylic acid-methylmethacrylate-30:70-copolymer of 135,000 mol. wt.,methacrylic acid-dimethylaminoethyl-methacrylate-ethylacrylate of750,000 mol. wt., methacrylic acid-methylmethacrylate-ethylacrylate of1,000,000 mol. wt., and ethylacrylate-methylmethacrylate-ethylacrylateof 550,000 mol. wt; and, (g) an enteric composition chosen from thegroup of cellulose acetyl phthalate, cellulose diacetyl phthalate,cellulose triacetyl phthalate, cellulose acetate phthalate,hydroxypropyl methylcellulose phthalate, sodium cellulose acetatephthalate, cellulose ester phthalate, cellulose ether phthalate,methylcellulose phthalate, cellulose ester-ether phthalate,hydroxypropyl cellulose phthalate, alkali salts of cellulose acetatephthalate, alkaline earth salts of cellulose acetate phthalate, calciumsalt of cellulose acetate phthalate, ammonium salt of hydroxypropylmethylcellulose phthalate, cellulose acetate hexahydrophthalate,hydroxypropyl methylcellulose hexahydrophthalate, polyvinyl acetatephthalate diethyl phthalate, dibutyl phthalate, dialkyl phthalatewherein the alkyl comprises from 1 to 7 straight and branched alkylgroups, aryl phthalates, and other materials known to one or ordinaryskill in the art.

Accordingly, in at least one other embodiment, the control-releasingcoat of osmotic dosage forms of the present invention comprises awater-insoluble water-permeable film-forming polymer, water-solublepolymer, and optionally a plasticizer and/or a pore-forming agent. Thewater-insoluble, water-permeable film-forming polymers useful for themanufacture of the control-releasing coat can be cellulose ethers, suchas for example, ethyl celluloses chosen from the group of ethylcellulose grade PR100, ethyl cellulose grade PR20 and any combinationthereof; cellulose esters, and polyvinyl alcohol. The water-solublepolymers useful for the control-releasing coat can be, for example,polyvinylpyrrolidone, hydroxypropyl methylcellulose and hydroxypropylcellulose.

The skilled artisan will appreciate that that the desired in-vitrorelease rates described herein for the bupropion salt can be achieved bycontrolling the permeability and/or the amount of coating applied to thecore of the osmotic dosage form. The permeability of thecontrol-releasing coat, can be altered by varying the ratio of thewater-insoluble, water-permeable film-forming polymer:water-solublepolymer:optionally the plasticizer and/or the quantity of coatingapplied to the core of the osmotic dosage form. A more extended releaseis generally obtained with a higher amount of water-insoluble,water-permeable film forming polymer. The addition of other excipientsto the core of the osmotic dosage form can also alter the permeabilityof the control-releasing coat. For example, if the core of the osmoticdosage form comprises a swellable polymer, the amount of plasticizer inthe control-releasing coat can be increased to make the coat morepliable as the pressure exerted on a less pliable coat by the swellablepolymer could rupture the coat. Further, the proportion of thewater-insoluble water-permeable film forming polymer and water-solublepolymer may also be altered depending on whether a faster or slowerin-vitro dissolution is desired.

In at least one other embodiment, the control-releasing coat of theosmotic dosage form comprises an aqueous dispersion of a neutral estercopolymer without any functional groups; a poly glycol having a meltingpoint greater than 55° C., and one or more pharmaceutically acceptableexcipients and cured at a temperature at least equal to or greater thanthe melting point of the poly glycol. The manufacture and use of suchcoating formulations are described in detail in US published patentapplication 20040037883A1, published on Feb. 26, 2004. In brief,examples of neutral ester copolymers without any functional groupscomprising the coat can be EUDRAGIT® NE30D, EUDRAGIT® NE40D (RohmAmerica LLC), or mixtures thereof. This coat can comprise hydrophilicagents to promote wetting of the coat when in contact withgastrointestinal fluids. Such hydrophilic agents include, for example,hydrophilic water-soluble polymers such as hydroxypropyl methylcellulose(HPMC), hydroxypropyl cellulose (HPC) and combinations thereof. The polyglycol can be, for example, chosen from the group of polyethylene glycol6000, polyethylene glycol 8000, polyethylene glycol 10000, polyethyleneglycol 20000, Poloxamer 188, Poloxamer 338, Poloxamer 407, PolyethyleneOxides, Polyoxyethylene Alkyl Ethers, and Polyoxyethylene Stearates, andcombinations thereof. This control-releasing coat of the osmotic dosageform can further comprise a pore-forming agent. The pore former,however, must be sufficiently insoluble in the aqueous dispersion, butmust be sufficiently soluble in the environment of use. One method forproducing such coats is detailed in European patent EP 1267842B1.

The control-releasing coat of certain embodiments of the osmotic dosageform of certain embodiments of the present invention includes at leastone polymer in an amount sufficient to achieve a controlled release ofthe bupropion salt. Examples of polymers that can be used in thecontrol-releasing coat of these embodiments include cellulose acetatephthalate, cellulose acetate trimaletate, hydroxy propyl methylcellulosephthalate, polyvinyl acetate phthalate, ammonio methacrylate copolymerssuch as those sold under the Trade Mark EUDRAGIT® RS and RL, polyacrylic acid and poly acrylate and methacrylate copolymers such as thosesold under the trademark EUDRAGIT® S and L, polyvinyl acetaldiethylaminoacetate, hydroxypropyl methylcellulose acetate succinate, shellac;hydrogels and gel-forming materials, such as carboxyvinyl polymers,sodium alginate, sodium carmellose, calcium carmellose, sodiumcarboxymethyl starch, poly vinyl alcohol, hydroxyethyl cellulose, methylcellulose, gelatin, starch, and cellulose based cross-linked polymers inwhich the degree of crosslinking is low so as to facilitate adsorptionof water and expansion of the polymer matrix, hydroxypropyl cellulose,hydroxypropyl methylcellulose, polyvinylpyrrolidone, crosslinked starch,microcrystalline cellulose, chitin, aminoacryl-methacrylate copolymer(EUDRAGIT® RS-PM, Rohm & Haas), pullulan, collagen, casein, agar, gumarabic, sodium carboxymethyl cellulose, (swellable hydrophilic polymers)poly(hydroxyalkyl methacrylate) (molecular weight 5K-5000K),polyvinylpyrrolidone (molecular weight 10K-360K), anionic and cationichydrogels, polyvinyl alcohol having a low acetate residual, a swellablemixture of agar and carboxymethyl cellulose, copolymers of maleicanhydride and styrene, ethylene, propylene or isobutylene, pectin(molecular weight 30K-300K), polysaccharides such as agar, acacia,karaya, tragacanth, algins and guar, polyacrylamides, POLYOX®polyethylene oxides (molecular weight 100K-5000K), AQUAKEEP® acrylatepolymers, diesters of polyglucan, crosslinked polyvinyl alcohol and polyN-vinyl-2-pyrrolidone, sodium starch glycolate (e.g. EXPLOTAB®; EdwardMandell C. Ltd.); hydrophilic polymers such as polysaccharides, methylcellulose, sodium or calcium carboxymethyl cellulose, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, nitrocellulose, carboxymethyl cellulose, cellulose ethers, polyethyleneoxides (e.g. POLYOX®, Union Carbide), methyl ethyl cellulose,ethylhydroxy ethylcellulose, cellulose acetate, cellulose butyrate,cellulose propionate, gelatin, collagen, starch, maltodextrin, pullulan,polyvinyl pyrrolidone, polyvinyl alcohol, polyvinyl acetate, glycerolfatty acid esters, polyacrylamide, polyacrylic acid, copolymers ofmethacrylic acid or methacrylic acid (e.g. EUDRAGIT®, Rohm and Haas),other acrylic acid derivatives, sorbitan esters, natural gums,lecithins, pectin, alginates, ammonia alginate, sodium, calcium,potassium alginates, propylene glycol alginate, agar, and gums such asarabic, karaya, locust bean, tragacanth, carrageens, guar, xanthan,scleroglucan and mixtures and blends thereof. In at least one embodimentof the osmotic dosage form of the present invention, the polymer is anacrylate dispersion such as EUDRAGIT® NE30D, EUDRAGIT® NE40D (RohmAmerica LLC), KOLLICOAT® SR 30D, SURELEASE®, or a mixture thereof. Thepolymer can be present in an amount of from 20% to 90% by weight of thecontrol-releasing coat, depending on the controlled release profiledesired. For example, in certain embodiments of the osmotic dosage form,the polymer is present in an amount of from 50% to 95%, in otherembodiments from 60% to 90%, and in still other embodiments 75% of thecontrol-releasing coat weight.

The control-releasing coat of certain embodiments of the osmotic dosageform of the present invention can also include one or morepharmaceutically acceptable excipients such as lubricants, emulsifiers,anti-foaming agents, plasticisers, solvents and the like.

Lubricants can be included in the control-releasing coat of certainembodiments of the osmotic dosage form of the present invention to helpreduce friction of coated microparticles during manufacturing. Thelubricants that can be used in the control-releasing coat include butare not limited to adipic acid, magnesium stearate, calcium stearate,zinc stearate, calcium silicate, magnesium silicate, hydrogenatedvegetable oils, sodium chloride, sterotex, polyoxyethylene, glycerylmonostearate, talc, polyethylene glycol, sodium benzoate, sodium laurylsulfate, magnesium lauryl sulfate, sodium stearyl fumarate, lightmineral oil, waxy fatty acid esters such as glyceryl behenate, (i.e.Compritol™), Stear-O-Wet™ and Myvatex™ TL. In at least one embodiment,the lubricant is selected from magnesium stearate and talc. Combinationsof these lubricants are operable. The lubricant(s) can each be presentin an amount of from 0.1% to 80% of the control-releasing coat weight.For example, in certain embodiments the lubricant is present in anamount of from 0.5% to 20%, in other embodiments from 0.8% to 10%, andin still other embodiments 1.5% of the control-releasing coat weight.

Emulsifying agent(s) (also called emulsifiers or emulgents) can beincluded in the control-releasing coat of the osmotic dosage forms ofcertain embodiments of the present invention to facilitate actualemulsification during manufacture of the coat, and also to increase orensure emulsion stability during the shelf-life of the product.Emulsifying agents useful for the control-releasing coat composition ofthe osmotic dosage form include, but are not limited to naturallyoccurring materials and their semi synthetic derivatives, such as thepolysaccharides, as well as glycerol esters, cellulose ethers, sorbitanesters (e.g. sorbitan monooleate or SPAN™ 80), and polysorbates (e.g.TWEEN™ 80). Combinations of emulsifying agents are operable. Theemulsifying agent(s) can be present in an amount of from 0.01% to 0.25%of the control-releasing coat weight. For example, in certainembodiments the emulsifying agent is present in an amount of from 0.01%to 0.15%, in other embodiments from 0.01% to 0.07%, and in still otherembodiments 0.03% of the control-releasing coat weight.

Anti-foaming agent(s) can be included in the control-releasing coat ofthe osmotic dosage form of certain embodiments of the present inventionto reduce frothing or foaming during manufacture of the coat.Anti-foaming agents useful for the control-releasing coat composition ofthe osmotic dosage form include, but are not limited to simethicone,polyglycol and silicon oil. In at least one embodiment the anti-foamingagent is Simethicone C. The anti-foaming agent can be present in anamount of from 0.01% to 10% of the control-releasing coat weight. Forexample, in certain embodiments the anti-foaming agent is present in anamount of from 0.05% to 1%, in other embodiments from 0.1% to 0.3%, andin still other embodiments 0.15% of the control-releasing coat weight.

It is contemplated that in certain embodiments, other excipientsconsistent with the objects of the present invention can also be used inthe control-releasing coat of the osmotic dosage form.

In at least one embodiment, the control-releasing coat of the osmoticdosage form includes 75% EUDRAGIT® NE30D, 1.5% Magnesium stearate, 1.5%Talc, 0.03% TWEEN™ 80, 0.15% Simethicone C, and 21.82% water, by weightof the control-releasing coat composition.

In a prophetic example of certain embodiments of osmotic dosage forms ofthe present invention, the manufacturing process for thecontrol-releasing coat of the osmotic dosage form can hypothetically beas follows: Water is split into two portions of 15% and 85%. Theanti-foaming agent and the emulsifying agent are then added to the 15%water portion, and mixed at 300 rpm to form portion A. In at least oneembodiment, the anti-foaming agent is Simethicone C, and the emulsifyingagent is TWEEN™ 80. A first lubricant is then added to the 85% waterportion and mixed at 9500 rpm to form portion B. In at least oneembodiment, the first lubricant is talc. Then portion A is mixed withportion B, a second lubricant is slowly added, and mixed at 700 rpmovernight. In at least one embodiment, the second lubricant is magnesiumstearate. Finally, an aqueous dispersion of a neutral ester copolymer isadded and mixed for 30 minutes at 500 rpm. In at least one embodiment,the aqueous dispersion of a neutral ester copolymer is EUDRAGIT® NE30D.The resultant coat solution can then be used to coat the osmoticsubcoated microparticles to a 35% weight gain with the followingparameters: An inlet temperature of from 10° C. to 60° C., preferablyfrom 20° C. to 40° C., and more preferably from 25° C. to 35° C.; anoutlet temperature of from 10° C. to 60° C., preferably from 20° C. to40° C., and more preferably from 25° C. to 35° C.; a product temperatureof from 10° C. to 60° C., preferably from 15° C. to 35° C., and morepreferably from 22° C. to 27° C.; an air flow of from 10 c·m/h to 180c·m/h, preferably from 40 c·m/h to 120 c·m/h, and more preferably from60 c·m/h to 80 c·m/h; and an atomizing pressure of from 0.5 bar to 4.5bar, preferably from 1 bar to 3 bar, and more preferably 2 bar. Theresultant coated microparticles can then be discharged from the coatingchamber and overcured with the following parameters: A curingtemperature of from 20° C. to 65° C., preferably from 30° C. to 55° C.,and more preferably 40° C.; and a curing time of from 2 hours to 120hours, preferably from 10 hours to 40 hours, and more preferably 24hours. Any other technology resulting in the coating formulation of thecontrol-releasing coat of the osmotic dosage form that is consistentwith the objects of the invention can also be used.

In at least one other embodiment, the osmotic dosage forms comprise awater-soluble or rapidly dissolving coat between the semipermeablemembrane and the control-releasing coat. The rapidly dissolving coat canbe soluble in the buccal cavity and/or upper GI tract, such as thestomach, duodenum, jejunum or upper small intestines. Materials suitablefor the manufacture of the water-soluble coat are disclosed in U.S. Pat.Nos. 4,576,604 and 4,673,405, and the text Pharmaceutical Dosage Forms:Tablets Volume I, Second Edition. A. Lieberman. ed. 1989, Marcel Dekker,Inc. In certain embodiments, the rapidly dissolving coat can be solublein saliva, gastric juices, or acidic fluids. Materials which aresuitable for making the water soluble coat or layer can comprise, forexample, water soluble polysaccharide gums such as carrageenan,fucoidan, gum ghatti, tragacanth, arabinogalactan, pectin, and xanthan;water-soluble salts of polysaccharide gums such as sodium alginate,sodium tragacanthin, and sodium gum ghattate; water-solublehydroxyalkylcellulosc wherein the alkyl member is straight or branchedof 1 to 7 carbons such as, for example, hydroxymethylcellulose,hydroxyethylcellulose, and hydroxypropylcellulose; syntheticwater-soluble cellulose-based lamina formers such as, for example,methyl cellulose and its hydroxyalkyl methylcellulose cellulosederivatives such as a member chosen from the group of hydroxyethylmethylcellulose, hydroxypropyl methylcellulose, and hydroxybutylmethylcellulose; croscarmellose sodium; other cellulose polymers such assodium carboxymethylcellulose; and other materials known to those ofordinary skill in the art. Other lamina forming materials that can beused for this purpose include, for example, poly(vinylpyrrolidone),polyvinylalcohol, polyethylene oxide, a blend of gelatin andpolyvinyl-pyrrolidone, gelatin, glucose, saccharides, povidone,copovidone, poly(vinylpyrrolidone)-poly(vinyl acetate) copolymer. Thewater soluble coating can comprise other pharmaceutical excipients thatdo or do not alter the way in which the water soluble coating behaves.The artisan of ordinary skill will recognize that the above-notedmaterials include film-forming polymers. The inert water-soluble coatcovering the semipermeable wall and blocking the passageway of osmoticdosage forms of the present invention, is made of synthetic or naturalmaterial which, through selective dissolution or erosion can allow thepassageway to be unblocked thus allowing the process of osmotic deliveryto start. This water-soluble coat can be impermeable to a first externalfluid, while being soluble in a second external fluid. This property canhelp to achieve a controlled and selective release of the bupropion saltfrom the osmotic dosage form so as to achieve the desired in-vitrorelease rates.

In embodiments where the core of the osmotic dosage form does notcomprise an osmagent, the osmotic dosage forms can comprise an osmoticsubcoat, which can surround the core of the osmotic dosage form. Theosmotic subcoat comprises at least one osmotic agent and at least onehydrophilic polymer. The osmotic subcoat of this embodiment provides forthe substantial separation of the bupropion salt from the osmotic agentinto substantially separate compartments/layers. This separation canincrease the stability of the bupropion salt by reducing possibleunfavorable interactions between the bupropion salt and the osmagent,and/or between the bupropion salt and the components of thecontrol-releasing coat. For example, the osmagent can be hygroscopic innature, and can attract water that can lead to the degradation of thebupropion salt. Since the osmotic agent of these embodiments can besubstantially separated from the bupropion salt, the bupropion salt canbe less prone to degradation from the water drawn in by the osmagent.The control-releasing coat comprises a control-releasing polymer andoptionally a plasticizer. The coated cores of the osmotic dosage formcan be filled into capsules, or alternatively can be compressed intotablets using suitable excipients. In these embodiments themultiparticulate osmotic dosage form can utilize both diffusion andosmosis to control drug release, and can be incorporated into sustainedrelease and/or delayed release dosage forms. In addition, in certainembodiments the osmotic pressure gradient and rate of release of thebupropion salt can be controlled by varying the level of the osmoticagent and/or the level of the hydrophilic polymer in the osmoticsubcoat, without the need for a seal coat around the osmotic subcoat.

The hydrophilic polymer used in an osmotic subcoat of certainembodiments of the present invention functions as a carrier for theosmotic agent. In certain embodiments the hydrophilic polymer in theosmotic subcoat does not substantially affect the drug release. In atleast one embodiment, the hydrophilic polymer used in the osmoticsubcoat does not act as a diffusion barrier to the release of thebupropion salt. In at least one embodiment the release profile of theosmotic agent is substantially the same as the release profile of thebupropion salt. Such hydrophilic polymers useful in an osmotic subcoatof the present invention include by way of example, polyvinylpyrrolidone, hydroxyethyl cellulose, hydroxypropyl cellulose, lowmolecular weight hydroxypropyl methylcellulose (HPMC), polymethacrylate,ethyl cellulose, and mixtures thereof. In at least one embodiment, thehydrophilic polymer of the osmotic subcoat is a low molecular weight anda low viscosity hydrophilic polymer. A wide variety of low molecularweight and low viscosity hydrophilic polymers can be used in the osmoticsubcoat. Examples of HPMC polymers that can be used in the osmoticsubcoat include PHARMACOAT® 606, PHARMACOAT® 606G, PHARMACOAT® 603,METHOCEL® E3, METHOCEL® E5, METHOCEL® E6, and mixtures thereof. Thehydrophilic polymer of the osmotic subcoat can be present in an amountof from 1% to 30% by weight of the osmotic subcoat composition. Forexample, in certain embodiments the hydrophilic polymer is present in anamount of from 1% to 20%, in other embodiments from 3% to 10%, and instill other embodiments 7% by weight of the osmotic subcoat composition.

In at least one embodiment, the osmotic subcoat comprises 7% PHARMACOAT®606, 1% sodium chloride, and 92% water, by weight of the osmotic subcoatcomposition.

One method for producing the osmotic subcoat can be as follows. The atleast one osmotic agent, for example sodium chloride, is dissolved inwater. The solution of osmotic agent and water is then heated to 60° C.The hydrophilic polymer is then added gradually to the solution. Amagnetic stirrer can be used to aid in the mixing of the hydrophilicpolymer to the solution of osmotic agent and water. The resultantosmotic subcoating solution can then be used to coat the core of theosmotic dosage form in a fluidized bed granulator, such as a granulatormanufactured by Glatt (Germany) or Aeromatic (Switzerland) to thedesired weight gain. An inlet temperature of from 10° C. to 70° C.,preferably from 30° C. to 55° C., and more preferably from 40° C. to 45°C.; an outlet temperature of from 10° C. to 70° C., preferably from 20°C. to 45° C., and more preferably from 30° C. to 35° C.; a producttemperature of from 10° C. to 70° C., preferably from 20° C. to 45° C.,and more preferably from 30° C. to 35° C.; an air flow of from 10 c·m/hto 180 c·m/h; preferably from 40 c·m/h to 120 c·m/h; and more preferablyfrom 60 c·m/h to 80 c·m/h; an atomizing pressure of from 0.5 bar to 4.5bar, preferably from 1 bar to 3 bar, and more preferably 2 bar; a curingtemperature of from 10° C. to 70° C., preferably from 20° C. to 50° C.,and more preferably from 30° C. to 40° C.; and a curing time of from 5minutes to 720 minutes; preferably from 10 minutes to 120 minutes, andmore preferably 30 minutes. Any other technology resulting in thecoating formulation of the osmotic subcoat consistent with the objectsof the invention can also be used.

The ratio of the components in the core, semipermeable membrane and/orwater-soluble membrane and/or at least one control-releasing coat and/orosmotic subcoat as well as the amount of the various membranes or coatsapplied can be varied to control delivery of the bupropion salt eitherpredominantly by diffusion across the surface of the semipermeablemembrane to predominantly by osmotic pumping through the at least onepassageway in the semipermeable membrane, and combinations thereof suchthat the dosage form can exhibit a modified-release, controlled-release,sustained-release, extended-release, prolonged-release, bi-phasicrelease, delayed-release profile or a combination of release profileswhereby the in-vitro release rates of the bupropion salt is such thatafter 2 hours from 0 to 20% by weight of the bupropion salt is released,after 4 hours from 15% to 45% by weight of the bupropion salt isreleased, after 8 hours, from 40% to 90% by weight of the bupropion saltis released, and after 16 hours, more than 80% by weight of thebupropion salt is released. In embodiments where the mode of exit of thebupropion salt comprises a plurality of pores, the amount of poreforming agent employed to achieve the desired in-vitro dissolution ratescan be readily determined by those skilled in the drug delivery art.

In at least one embodiment, the core of the osmotic dosage formcomprises bupropion hydrobromide. The proportion of the bupropionhydrobromide in the core can be from 40% to 99%, such as for example,40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 99% of thecore dry weight.

In certain embodiments, the core of the osmotic dosage form comprises atleast one means for increasing the hydrostatic pressure inside themembrane or coat. The membrane or coat can be a semipermeable membrane,a control-releasing coat, a water-soluble coat, an osmotic subcoat, orany combination thereof. The core of the osmotic dosage form has aneffective osmotic pressure greater than that of the surrounding fluid inthe environment of use so that there is a net driving force for water toenter the core. The at least one means for increasing the hydrostaticpressure inside the membrane or coat can be any material that increasesthe osmotic pressure of the core of the osmotic dosage form. The atleast one means for increasing the hydrostatic pressure inside themembrane or coat can be, for example, the bupropion salt, an osmagent,any material which can interact with water and/or an aqueous biologicalfluid, swell and retain water within their structure, such as forexample an osmopolymer, and any combination thereof. The osmagent can besoluble or swellable. Examples of osmotically effective solutes areinorganic and organic salts and sugars. The bupropion salt can itself bean osmagent or can be combined with one or more other osmagents, such asfor example, magnesium sulfate, magnesium chloride, sodium chloride,lithium chloride, potassium sulfate, sodium carbonate, sodium sulfite,lithium sulfate, potassium chloride, calcium carbonate, sodium sulfate,calcium sulfate, potassium acid phosphate, calcium lactate, d-mannitol,urea, inositol, magnesium succinate, tartaric acid, water soluble acids,alcohols, surfactants, and carbohydrates such as raffinose, sucrose,glucose, lactose, fructose, algin, sodium alginate, potassium alginate,carrageenan, fucoridan, furcellaran, laminaran, hypnea, gum arabic, gumghatti, gum karaya, locust bean gum, pectin, starch and mixturesthereof. In certain embodiments the amount of osmagent can range from,for example, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85,90, or 95% of the core dry weight.

The osmagent useful in certain embodiments of the present invention canbe any agent that can generate an osmotic pressure gradient for thetransport of water from the external environment of use into the osmoticdosage form. Osmagents are also known as osmotically effectivecompounds, osmotic solutes, and osmotic fluid imbibing agents. Osmagentsuseful in certain embodiments of the present invention are soluble inaqueous and biological fluids, such as ionizing compounds, inherentlypolar compounds, inorganic acids, organic acids, bases and salts. In atleast one embodiment the osmagent is a solid and dissolves to form asolution with fluids imbibed into the osmotic dosage form. A widevariety of osagents can be used to provide the osmotic pressure gradientused to drive the bupropion salt from the core of the osmotic dosageform. Examples of inorganic salts useful as osmagents include lithiumchloride, lithium sulfate, lithium phosphate, magnesium chloride,magnesium sulfate, potassium chloride, potassium sulfate, potassiumphosphate, potassium acid phosphate, sodium chloride, sodium sulfate,sodium phosphate, sodium sulfite, sodium nitrate, sodium nitrite, andmixtures thereof. Examples of salts of organic acids useful as osagentsinclude sodium citrate, potassium acid tartrate, potassium bitartrate,sodium bitartrate, and mixtures thereof. Examples of ionizable solidacids useful as osmagents include tartaric, citric, maleic, malic,fumaric, tartronic, itaconic, adipic, succinic, mesaconic acid, andmixtures thereof. Examples of other compounds useful as osmagentsinclude potassium carbonate, sodium carbonate, ammonium carbonate,calcium lactate, mannitol, urea, inositol, magnesium succinate,sorbitol, and carbohydrates such as raffinose, sucrose, glucose,lactose, lactose monohydrate, a blend of fructose glucose and mixturesthereof. In at least one embodiment the osmagent is selected from sodiumchloride, sodium bromide, sodium bisulfate, potassium acid tartrate,citric acid, mannitol, sucrose and mixtures thereof. Combinations ofthese osmagents is permissible. The osmagent can be present in an amountof from 0.1% to 50% of the dosage form weight. For example, in certainembodiments the osmagent is present in an amount of from 1% to 40%, andin other embodiments from 1% to 20% of the dosage form weight.

In certain embodiments, the at least one means for increasing thehydrostatic pressure can comprise, in addition to an osmagent, anymaterial which can interact with water and/or an aqueous biologicalfluid, swell and retain water within their structure. In certainembodiments where the at least one means for increasing the hydrostaticpressure is an osmopolymer, which can be slightly cross-linked oruncross-linked. The uncross-linked polymers to be used as osmopolymers,when in contact with water and/or aqueous biological fluid, should notdissolve in water, hence maintaining their physical integrity. Suchpolymers can be, for example, chosen from the group of polyacrylic acidderivatives (e.g., polyacrylates, poly-methyl methacrylate, poly(acrylicacid) higher alkyl esters, poly(ethylmethacrylate), poly(hexadecylmethacrylate-co-methylmethacrylate), poly(methylacrylate-co-styrene),poly(n-butyl methacrylate), poly(n-butyl-acrylate), poly(cyclododecylacrylate), poly(benzyl acrylate), poly(butylacrylate),poly(secbutylacrylate), poly(hexyl acrylate), poly(octyl acrylate),poly(decyl acrylate), poly(dodecyl acrylate), poly(2-methyl butylacrylate), poly(adamantyl methacrylate), poly(benzyl methacrylate),poly(butyl methacrylate), poly(2-ethylhexyl methacrylate), poly(octylmethacrylate), acrylic resins), polyacrylamides, poly(hydroxy ethylmethacrylate), poly(vinyl alcohol), poly(ethylene oxide), polyN-vinyl-2-pyrrolidone, naturally occurring resins such aspolysaccharides (e.g., dextrans, water-soluble gums, starches,chemically modified starches), cellulose derivatives (e.g., celluloseesters, cellulose ethers, chemically modified cellulose,microcrystalline cellulose, sodium carboxymethylcellulose andmethylcellulose), starches, CARBOPOL™, acidic carboxy polymer,CYANAMER™, polyacrylamides, cross-linked water-swellable indene-maleicanhydride polymers, GOOD-RITE™, polyacrylic acid, polyethyleneoxide,starch graft copolymers, AQUA-KEEPS™, acrylate polymer, diestercross-linked polyglucan, and any combination thereof.

In certain embodiments, the core of the osmotic dosage form furthercomprises a means for forcibly dispensing the bupropion salt from thecore to the exterior of the dosage form. The at least one means forforcibly dispensing the bupropion salt can be any material which canswell in water and/or aqueous biological fluid and retain a significantfraction of water within its structure, and will not dissolve in waterand/or aqueous biological fluid, a means for generating a gas, anosmotically effective solute or any combination thereof which canoptionally be surrounded by a membrane or coat depending on theparticular means used. The membrane or coat can be, for example, amembrane or coat that is essentially impermeable to the passage of thebupropion salt, gas and compounds, and is permeable to the passage ofwater and/or aqueous biological fluids. Such a coat or membranecomprises, for example, a semipermeable membrane, microporous membrane,asymmetric membrane, which asymmetric membrane can be permeable,semipermeable, perforated, or unperforated. In at least one embodiment,the at least one means for forcibly dispensing the bupropion salt fromthe core of the osmotic dosage form comprises a means for generatinggas, which means for generating gas is surrounded by, for example, asemipermeable membrane. In operation, when the gas generating meansimbibes water and/or aqueous biological fluids, the means for generatinggas reacts and generates gas, thereby enlarging and expanding the atleast one means for forcibly dispensing the bupropion saltunidirectionally or multidirectionally. The means for generating a gascomprises any compound or compounds, which can produce effervescence,such as for example, at least one solid acid compound and at least onesolid basic compound, which in the presence of a fluid can react to forma gas, such as for example, carbon dioxide. Examples of acid compoundsinclude, organic acids such as malic, fumaric, tartaric, itaconic,maleic, citric, adipic, succinic and mesaconic, and inorganic acids suchas sulfamic or phosphoric, also acid salts such as monosodium citrate,potassium acid tartrate and potassium bitartrate. The basic compoundsinclude, for example, metal carbonates and bicarbonates salts, such asalkali metal carbonates and bicarbonates. The acid and base materialscan be used in any convenient proportion between 1 to 200 parts of theat least one acid compound to the at least one basic compound or 1 to200 parts of the at least one basic compound to the at least one acidcompound. The means for generating gas is described, for example in U.S.Pat. No. 4,235,236.

In at least one embodiment, the at least one means for forciblydispensing the bupropion salt form the core of the osmotic dosage formcomprises any material which can swell in water and/or aqueousbiological fluid and retain a significant fraction of water within itsstructure, and will not dissolve in water and/or aqueous biologicalfluid, such as for example, a hydrogel. Hydrogels include, for example,lightly cross-linked hydrophilic polymers, which swell in the presenceof fluid to a high degree without dissolution, usually exhibiting a5-fold to a 50-fold volume increase. Examples of hydrogels includepoly(hydroxyalkyl methacrylates), poly(acrylamide),poly(methacrylamide), poly(N-vinyl-2-pyrrolidone), anionic and cationichydrogels, polyelectrolyte complexes, a water-insoluble, water-swellablecopolymer produced by forming a dispersion of finely divided copolymersof maleic anhydride with styrene, ethylene, propylene butylene orisobutylene cross-linked with from 0.001 to 0.5 moles of apolyunsaturated cross-linking agent per mole of maleic anhydride in thecopolymer as disclosed in U.S. Pat. No. 3,989,586, the water-swellablepolymers or N-vinyl lactams as disclosed in U.S. Pat. No. 3,992,652,semi-solid cross-linked poly(vinyl pyrrolidone), diester cross-linkedpolyglucan hydrogels as described in U.S. Pat. No. 4,002,173, theanionic hydrogels of heterocyclic N-vinyl monomers as disclosed in U.S.Pat. No. 4,036,788, the ionogenic hydrophilic gels as described in J.Biomedical Mater, Res., Vol. 7, pages 123 to 126, 1973, and the like.Some of the osmopolymers and hydrogels are interchangeable Such meanscan optionally be covered by a membrane or coat impermeable to thepassage of the bupropion salt, and compounds, and is permeable to thepassage of water and/or aqueous biological fluids. Such a coat ormembrane comprises, for example, a semipermeable membrane, microporousmembrane, asymmetric membrane, which asymmetric membrane can bepermeable, semipermeable, perforated, or unperforated.

In at least one other embodiment, the at least one means for forciblydispensing the bupropion salt from the core of the osmotic dosage formcomprises at least one osmotically effective solute surrounded by amembrane or coat impermeable to the passage of the bupropion salt, andcompounds, and is permeable to the passage of water and/or aqueousbiological fluids such that the osmotically effective solute exhibits anosmotic pressure gradient across a membrane or coat. Such coat ormembrane comprises, for example, a semipermeable membrane, microporousmembrane, asymmetric membrane, which asymmetric membrane can bepermeable, semipermeable, perforated, or unperforated. The osmoticallyeffective solutes include, for example, the osmagents described above.

In embodiments of the osmotic dosage form where the means for forciblydispensing the bupropion salt is surrounded by a membrane or coat, atleast one plasticizer can be added to the membrane composition to impartflexibility and stretchability to the membrane or coat. In embodimentswhere the means for forcibly dispensing the bupropion salt comprises ameans for generating a gas, the membrane or coat should be stretchableso as to prevent rupturing of the membrane or coat during the period ofdelivery of the bupropion salt. U.S. Pat. No. 4,235,236 describes themanufacture of such a membrane or coat. Plasticizers, which can be usedin these embodiments include, for example, cyclic and acyclicplasticizers, phthalates, phosphates, citrates, adipates, tartrates,sebacates, succinates, glycolates, glycerolates, benzoates, myristates,sulfonamides halogenated phenyls, poly(alkylene glycols),poly(alkylenediols), polyesters of alkylene glycols, dialkyl phthalates,dicycloalkyl phthalates, diaryl phthalates and mixed alkyl-arylphthalates, such as for example, dimethyl phthalate, dipropyl phthalate,di(2-ethylhexyl)phthalate, di-isopropyl phthalate, diamyl phthalate anddicapryl phthalate; alkyl and aryl phosphates, such as for example,tributyl phosphate, trioctyl phosphate, tricresyl phosphate, trioctylphosphate, tricresyl phosphate and triphenyl phosphate; alkyl citrateand citrates esters such as tributyl citrate, triethyl citrate, andacetyl triethyl citrate; alkyl adipates, such as for example, dioctyladipate, diethyl adipate and di(2-methoxyethyl)adipate; dialkyltartrates, such as for example, diethyl tartrates and dibutyl tartrate;alkyl sebacates, such as for example, diethyl sebacate, dipropylsebacate and dinonyl sebacate; alkyl succinates, such as for example,diethyl succinate and dibutyl succinate; alkyl glycolates, alkylglycerolates, glycol esters and glycerol esters, such as for example,glycerol diacetate, glycerol triacetate, glycerol monolactate diacetate,methyl phthalyl ethyl glycolate, butyl phthalyl butyl glycolate,ethylene glycol diacetate, ethylene glycol dibutyrate, triethyleneglycol diacetate, triethylene glycol dibutyrate, triethylene glycoldipropionate and mixtures thereof. Other plasticizers include camphor,N-ethyl (o- and p-toulene) sulfonamide, chlorinated biphenyl,benzophenone, N-cyclohexyl-p-toluene sulfonamide, substituted epoxidesand mixtures thereof.

The at least one means for forcibly dispensing the bupropion salt fromthe core of certain embodiments of the osmotic dosage form can belocated such that it is approximately centrally located within the coreof the osmotic dosage form and is surrounded by a layer comprising thebupropion salt. Such a configuration is disclosed in U.S. Pat. No.6,352,721. Alternatively, the core of the osmotic dosage form comprisesat least two layers in which the first layer comprises the bupropionsalt, osmagent and/or osmopolymer and optionally at least onepharmaceutically acceptable excipient adjacent to a second layercomprising the means for forcibly dispensing the bupropion salt.Alternatively, the core of the osmotic dosage form comprises amultilayered structure in which the layer comprising the bupropion saltis sandwiched between two layers of the means for forcibly dispensingthe bupropion salt from the osmotic dosage form.

Combinations

The present invention also contemplates combinations of the bupropionsalt with at least one other drug. For example, a composition isprovided which comprises a first component of bupropion hydrobromide,and a second component of at least one other drug, wherein the twocomponents are present in an amount effective in the treatment of acondition. The present invention further provides a method for treatinga condition, comprising administering to a patient an effective amountof a first component of bupropion hydrobromide in combination with aneffective amount of at least one other drug. The skilled artisan willknow or can determine by known methods which drug combinations areacceptable. Types of drugs that may be selected as the second druginclude by way of example other depressants, anti-anxiety agents,steroidal and non-steroidal inflammatories, SSRIs, anti-migraine agents,anti-pain agents, anti-emetics, drugs for treating abuse such asnicotine, appetite modulators, anti-virals, vasodilators, anti-painagents, et al. For example, the other drug can be an antidepressantselected from: monoamine oxidase (MAO) inhibitor, tricyclicantidepressant, serotonin reuptake inhibitor, selective norepinephrinereuptake inhibitors (SNRIs), aminoketones, serotonin antagonists,dopamine reuptake inhibitors, dual reuptake inhibitors, norepinephrineenhancers, serotonin activity enhancers, dopamine activity enhancers,and combinations thereof. Examples of other drugs that can be combinedwith bupropion hydrobromide include citalopram, escitalopram,venlafaxine, clozapine, melperone, amperozide, iloperidone, risperidone,quetiapene, olanzapine, ziprasidone, aripiprazole, reboxetine, VIAGRA®,sertraline, paroxetine, fluoxetine, gabapentin, valproic acid,amitriptyline, lofepramine, fluvoxamine, imipramine, mirtazapine,nefazodone, nortriptyline, SAM-E and combinations thereof. In at leastone embodiment, a combination of bupropion hydrobromide and citalopramis provided. In at least one other embodiment, a combination ofbupropion hydrobromide and escitalopram is provided. In at least oneother embodiment a combination of bupropion hydrobromide and venlafaxineis provided.

In certain embodiments, combination products can be made by providing anovercoat to substantially surround the control-releasing coat of eachmicroparticle. In certain embodiments, a pulsatile release of at leastone other drug is achieved from the coated microparticles. This overcoatcan be an immediate release overcoat that includes at least one otherdrug and at least one low viscosity hydrophilic polymer. Thelow-viscosity polymer provides for the immediate release of the otherdrug from the overcoat. In at least one embodiment, the low-viscositypolymer used in the overcoat is hydroxypropyl methylcellulose (HPMC).The overcoat can also include a lubricant such as talc. As such, thisembodiment can provide an immediate release of at least one other drugfrom the overcoat in a first phase of drug release, and then asubsequent controlled release of the bupropion hydrobromide from thecontrol-releasing coated microparticle in a second phase of drugrelease.

In addition, combinations of microparticles of the invention each with adifferent functional coating can be combined together in a dosage form.For example, by combining a first group of uncoated, taste-masked orenteric coated microparticles with a second group of delayed orsustained release coated microparticles, a pulsatile drug releaseprofile or chronotherapeutic profile can be achieved. (e.g. see U.S.Pat. No. 5,260,068, U.S. Pat. No. 6,270,805, U.S. Pat. No. 6,926,909,US2002/0098232, US2004/0197405, U.S. Pat. No. 6,635,284, or U.S. Pat.No. 6,228,398).

In other embodiments, the combination may comprise at least 2 differentmicroparticles one of which contain bupropion hydrobromide and the otherthe second drug which are comprised in a capsule formulation.

While only specific combinations of the various features and componentsof the present invention have been discussed herein, it will be apparentto those of skill in the art that desired subsets of the disclosedfeatures and components and/or alternative combinations of thesefeatures and components can be utilized as desired.

As will be seen from the non-limiting examples described below, thecoatings of the invention are quite versatile. For example, the lengthand time for the lagtime can be controlled by the rate of hydration andthe thickness of the control-releasing coat. It is possible to regulatethe rate of hydration and permeability of the control-releasing coat sothat the desired controlled-release profile can be achieved. There is nogeneral preferred control-releasing coat thickness, as this will dependon the controlled release profile desired. Other parameters incombination with the thickness of the control-releasing coat includevarying the concentrations of one or more of the ingredients of thecontrol-releasing coat composition, varying the curing temperature andlength of time for curing the coated tablet microparticles, and incertain embodiments, varying the level of osmotic agent. The skilledartisan will know which parameters or combination of parameters tochange for a desired controlled release profile.

4. Stability Studies

The enhanced stability of the bupropion hydrobromide, in particularcompared to bupropion HCl, is clearly evident from degradation studiesperformed on the active pharmaceutical ingredient (API), alone, in thepresence of excipients and in the form of XL tablets. The results aredescribed in greater detail in the examples below.

The term “enhanced stability”, “greater stability”, “increasedstability” or “more stable” as used herein means that the bupropion salt(bupropion hydrobromide), and compositions, formulations or medicamentscomprising the bupropion salt, when exposed to like conditions, i.e.,storage for at least 3, 4, 5 and/or at least 6 months under acceleratedtorage conditions, i.e., 40 degrees C. at 75% relative humidity showless degradation as determined by the formation of at least onedegradation product characteristic of bupropion degradation and/or theretention of potency, compared to otherwise similar compositionscontaining bupropion hydrochloride. This includes in particularcompositions containing bupropion hydrobromide that show lessdegradation based on a reduced amount of at least one compoundcharacteristic of bupropion degradation relative to an otherwise similarbupropion hydrochloride composition stored under similar acceleratedstorage conditions i.e., 40 degrees C. at 75% humidity for at least 3months, 4 months, 5 months and/or at least 6 months. Additionallyanother indicator of enhanced stability is that the bupropion HBrcomposition exhibits less fluctuation is an in vitro dissolution profilewhich shows less fluctuation relative to an otherwise similar bupropionHCl composition after prolonged storage under similar conditions andwherein dissolution is assayed under similar conditions (media and time)particularly after being stored for at least 3 months, 4 months, 5months and/or at least 6 months at 40 degrees C. and 75% relativehumidity.

By “less degradation” it is meant any measurable decrease in the amountof at least one impurity or degradation product characteristic ofbupropion degradation or any measurable difference (enhancement orreduced fluctuation) in potency relative to an otherwise similarbupropion HCl composition after the compositions are stored forprolonged time, i.e., at least 3 months, 4 months, 5 months and/or atleast 6 months at 40 degrees C. at 75% relative humidity. The“degradation products” include those listed on page 281 of the 26thedition of the USP and any other degradation products that may appear aspeaks on a chromatogram during the assay. One indicator of enhancedpotency is a bupropion HBr composition that exhibits less fluctuation indissolution profile after prolonged storage, i.e at least 3, 4, 5 or 6months at 40 degrees C. and 75% relative humidity relative to anotherwise similar bupropion HCl composition assayed under similardissolution conditions.

A comparison of the stability of several bupropion salts, including theHBr, HCl, maleate, tosylate, fumarate, succinate, tartrate and citratesalts, was performed by placing these salts in both open and closedvials in a stability chamber kept at 40 degrees C. and 75% relativehumidity for various periods of time. The stability of the salts wasevaluated based on the formation of the main degradation products (seebelow) as determined by HPLC analysis and the % potency (or assay) ofthe API, after specific time periods in the stability chamber. Theeffect of the addition of solvents, such as water, ethanol and isopropylalcohol, was also studied.

The results unequivocally show that after at least 3 months or after atleast 6 months the HBr salt of bupropion, on average, showed the leastamount of degradation products and retained the highest activity of allof the salts tested. Accordingly the HBr salt possesses the greateststability. These results are unexpected and would be in no waypredictable by a person skilled in the art since none of the other saltsthat were tested showed this enhanced stability.

Further stability tests were performed by directly comparing bupropionHBr and bupropion HCl salts in forced degradation studies. These studieswere performed in closed bottles in a stability chamber kept at 40degrees C. and 75% relative humidity. At specified times, the materialin the bottles was analyzed for the presence of degradation products and% potency (% assay). It was unexpectedly found that the amount ofimpurities was consistently lower and the % potency was consistentlyhigher for the HBr salt compared to the HCl salt.

Forced degradation studies were also performed on bupropion HBr andbupropion HCl API's in the presence of standard excipients used inpharmaceutical formulations. The amount of the main degradation productswas observed at 24 and 48 hours after treatment at 55° C., at 55° C. and100% relative humidity and at 105 degrees C. Once again, it wasunexpectedly found that the HBr salt showed the lowest amount ofdegradation (as determined by the formation of impurities) under theseconditions.

The stability of the tablet formulations of bupropion HCl and HBr saltswas also compared. With both salts, a tablet having the firstcontrol-releasing (EC) coat as well as a double coated tablet (with acontrol-releasing and moisture barrier coat) were evaluated. The tabletswere placed individually on an open dish, and exposed to the acceleratedconditions of 40° C. and 75% relative humidity in a stability chamber.After 13 and 20 days, the samples were assayed and impurity analysis wasperformed.

For the single coated bupropion HCl tablets, the main degradationimpurities 3-CBZ and 852U77 were 0.12% and 0.38% respectively, whereas,for the bupropion HBr tablets, these values were 0.07% and 0.49%respectively. The other degradation impurities and the total unknownswere very similar for both products; however, the assay value for theHBr product was higher than the HCl. The difference in the assay and theimpurity levels were more significant in the double coated tabletsproducts. For the same period of the study the assay of the BupropionHCl was lower (95.5% compared to 98.6 for bupropion HBr) and the levelof the degradation and total unknowns were higher (3-CBZ: 0.28%, 852U77:1.23%, 827U76: 0.10% and total 1.73%) than the Bupropion HBr (3-CBZ:0.12%, 852U77: 0.41%, 827U76: 0.05% and total 0.75%).

The stability studies performed herein have clearly demonstrated theunexpected enhanced stability of buproprion HBr, in particular comparedto bupropion HCl, which is used in all pharmaceutical forms currentlyavailable. This enhanced stability is seen with the API form alone, theAPI form plus excipients and the extended release and enhancedabsorption tablets. Therefore pharmaceutical formulations comprisingbupropion HBr are not only new, but also inventive due to theirunexpected and beneficial enhanced stability properties. Pharmaceuticalformulations comprising bupropion HBr will show enhanced shelf life andwill withstand storage at higher temperatures and humidity levelscompared with the currently used bupropion HCl formulations.

5. Polymorphic Forms

It is well known that organic molecules can crystallize into solidforms. Moreover the same organic compound may assume differentcrystalline arrangements in solid form, depending on the conditionsunder which the crystal product is formed. This phenomenon is commonlyknown as polymorphism. A study was undertaken to explore the polymorphicforms of bupropion hydrobromide. The crystal forms of the productsobtained in this study were determined by powder X-ray diffraction(PXRD). A RIGAKU miniflex instrument (Radiation Cu K∝, generator 30 KV,filter Ni) was used to obtain the PXRD data.

A standard procedure was established to generate bupropion hydrobromide,this standard procedure produces a first polymorphic form which has beentermed polymorphic form I. The relative PXRD for form I is shown in FIG.54 and the differential scanning calorimetry (DSC) profile is shown inFIG. 55.

Bupropion HBr of form I has been used as the starting material inexperiments to identify other polymorphic forms. Two additionalpolymorphic forms were identified and have been named form II and formIII. FIGS. 56 and 57 show the PXRD data and DSC profile respectively ofpolymorphic form II. FIGS. 58 and 59 shown the PXRD data and DSC profilerespectively of form III.

Polymorphic form II was obtained by recrystallization of form 1 fromsolvents or mixtures of solvents such as acetone-water, methanol,dichloromethane, toluene-methanol and dimethylcarbonate-methanol.Polymorphic form III was obtained by recrystallization of polymorphicform I in methanol. Table 80 provides a list of recrystallizationconditions and the polymorphic form obtained under each set ofconditions.

The three polymorphic forms were subjected to stability testing. Samplesof the polymorphic forms were subjected to ICH conditions (40° C., 75%R.H.) and PXRD data was obtained at 3 months and 6 months. All of thesamples had the same PXRD profile indicating that this polymorphic formis stable at these conditions and is not changing or degrading. Samplesof the polymorphic forms II and III were tested after 1 month under thesame accelerated stability conditions. Polymorphic form II showed nochange in the PXRD profile at that time while the PXRD profile of formIII showed conversion to form II. This data suggests that polymorphicforms I and II are quite stable while polymorphic form III is not asstable as forms I and II under the test conditions.

Tables 99-104 contain exemplary 348 and 174 Bupropion HBr XL tabletsaccording to the invention. Table 105 contains stability data forexemplary bupropion HBr formulations under accelerated conditions fordifferent batches over different time periods.

As will be seen from the non-limiting examples described below, thecoatings used in the present invention are quite versatile. For example,the length and time for the lagtime can be controlled by the rate ofhydration and the thickness of the modified release overcoat. Otherparameters in combination with the thickness of the coatings includevarying the concentrations of some of the ingredients of the coatingcompositions of the invention described and/or varying the curingtemperature and length of curing the coated tablet cores. The skilledartisan will know which parameters or combination of parameters tochange for a desired controlled release profile.

The following examples illustrate the present invention and are notintended to limit the scope of the present invention.

EXAMPLES Example 1

Preparation of Buproprion HBr Salt

Buproprion HBr salt was prepared according to the method shown in Scheme1:

(a) Bromination and Condensation Reactions

3-Chloro-propiophenone starting material was brominated in methylenechloride by dropping bromine under controlled conditions. On reactioncompletion the mother liquor was worked up and then the second reactionwas executed by transferring the bromoderivative solution onto thetert-butylamine. The second substitution reaction (the tert-butylamineamino-group substitutes the bromine atom) forms the final bupropionmolecule. After work up of the mother liquor, a bupropion toluenesolution was obtained. The solvent was evaporated and bupropion wasdissolved in isopropanol. From the isopropanol solution, thehydrobromide was precipitated with hydrogen bromide gas. Onprecipitation completion, the product was centrifuged, washed withisopropanol and dried under vacuum. On dryer discharge approval it wasdischarged in Kraft drums within double polyethylene bags.

In the last finishing step, the above intermediate was sieved to obtainthe Final Release which was packed in Kraft drums within doublepolyethylene bags.

Elemental analysis of the bupropion HBr was carried out using a FisonsElemental Analyser EA 1108. The results were consistent with themolecular formula of bupropion HBr.

Example 2 Physiochemical Characterization of Burpopion Salts

The following bupropion salts were characterized against the HCl salt:

Potency (HPLC) Determined Product ID Lot# Quantity by R&D Bupropionmaleate 030/018 100 g  99.7% Bupropion tosylate 030/011/A 50 g 97.4%Bupropion Fumarate 031/1 10 g 89.8% Bupropion HBr 031/2 10 g 99.7%Bupropion succinate 031/3 10 g 97.6% Bupropion tartrate acid 031/5 10 g84.9% Bupropion tartrate neutral 031/5B 10 g 51.7%* Bupropion citrate031/8 10 g 85.0% *uncorrected for potency

Thermal Analysis (DSC) Samples:

2-5 mg of each salt was placed in an aluminum pan and covered with itslid. DSC was run for each sample at the rate of 10° C./min (for HBrsalt, different rates were used to investigate for polymorphs) from 30°C. to 400° C. TGA was also used for each of the HBr, HCl, maleate andtosylate salts.

Results and Discussion: Physicochemical Data:

The eight salts were first evaluated by HPLC, KF, pH and DSC for purity,water content, aqueous pH and possible polymorphs. As shown in the Table1, only the maleate, tosylate, HBr and succinate salts were sufficientlypure, the assay of others ranged between 51.7%% to 89.8%.

The salts were analyzed by DSC (at 10° C./min from 30° C. up to 400° C.)and the pH (aq. 0.5%), and the moisture content by KF were alsomeasured. The TGA was performed on the HCl, maleate, tosylate and HBrsalts.

Maleate: DSC showed a melting endothermic peak at the onset temperature199.1° C. and a smaller sharp peak at 205° C. The moisture content was0.10% and the pH of the aqueous solution of 0.5% was 4.29.

By re-crystallization in isopropyl alcohol (IPA)/EtOAc, the smaller peakalmost disappeared. The TGA showed that this product was thermallystable to at least 150° C. as 1.3% weight lost between room temperatureand 100° C. was observed. Like Bupropion HCl, no glass transition wasobserved when a heat-cool-heat experiment was done by TA instrument.

Fumarate: DSC showed multiple endothermic peaks at different onsettemperatures (172.3, 182.3, 202 and 217° C.). The moisture content was0.09% and the pH of the aqueous solution of 0.5% was 3.84.

Tosylate: DSC showed a melting endothermic peak at the onset temperature150° C., a smaller peak at 90° C. and multiple peaks at highertemperature (>200° C., probably decomposition). The peak at 90° C. wasprobably due to the solvent isopropyl acetate. The moisture content was1.71% and the pH of the aqueous solution of 0.5% was 5.56.

By re-crystallization in acetonitrile/hexane or acetonitrile/EtOAc, thesmall peak at 90° C. disappeared, the moisture content dropped to 0.23%,and the pH changed to 5.88. After two months, the re-crystallized samplewas retested for moisture content and found to be 0.18%. Therefore,there was a difference between the original and the re-crystallized saltin terms of purity and moisture content (originally thought to behydrated and/or hygroscopic).

The TGA showed that this product was not thermally stable as 1.3% weightlost was observed between room temperature and 100° C. Also the samplegave a residue of 10.3% at 400° C. as compared to minimal residues forbupropion HCl and maleate. The Heat-Cool-Heat experiment was done by TAinstrument showed a glass transition (Tg) at 45C. The Tg indicates thatthe morphology is amorphous rather than crystalline.

HBr: DSC showed melting endothermic peak at temperature 224° C., with ashoulder peak. The sample was run at different temperature rates, 1, 10,15 & 20° C./min to seek for possible polymorphs. No significantdifferences were observed for the endothermic peak shape at differenttemperature rates. By-crystallization of the HBr salt in differentsolvents or by internal synthesis starting from 3-chloropropiophenone,no improvements in the shape of the endothermic peak melting at −224° C.was observed (i.e, still the same shoulder at 10° C. or higher rates). AHeat-Cool-Heat experiment was done by TA instrument showed a glasstransition (Tg) at 23° C.

The moisture content was 0.00% and the pH of the aqueous solution of0.5% was 5.92.

Other salts: The DSC results of other salts show multiple meltingendothermic peaks. The pH, and the water content of all of the salts areshown in Table 2.

A comparison of the solubility & other physical properties of bupropionHBr vs bupropion HCl is presented in Table 3.

Hygroscopicity of Bupropion HBr:

The Dynamic Vapour Sorption (DVS) analysis of bupropion HBr suggeststhat the sample is a crystalline anhydrate and has very little wateruptake capacity (i.e. non-hygroscopic). The sample of bupropion HBrshows no significant water uptake over the range 0% RH-90% RH. Themaximum water uptake was measured at 0.14% weight at 90% RH. A DVSprofile for bupropion HBr is shown in FIG. 1 and DVS isotherm data forbupropion HBr is shown in FIG. 2.

Example 3 Forced Degradation Stability Study

The samples of each salt and the spiked salts with the bupropion HCl XLwere prepared under the conditions mentioned in Table 4. The sampleswere placed in the stability chamber at 40° C./75% RH, pulled out at 10,20 and 32 days and analyzed by HPLC for assay and impurities. Thestability of the bupropion salts were evaluated based on the formationof the main degradation product 3-chlorobenzoic acid (3-CBZ) and theintermediate degradation products diketone 827U76 and the ketohydroxylderivatives (20U78 and 852U77) (Scheme 2). The 3-chlorobenzoic acid isformed as a result of the oxidation/hydrolysis of the parent compoundbupropion salts.

As mentioned above, the stability samples were prepared in 2 mL vialsand used directly for assay and impurity analysis by HPLC withoutfurther sample preparations to minimize errors.

The 10 days forced degradation studies on these salts showed that thesuccinate, tartrate and citrate (with or without mixing with excipientsin closed vials) were not stable under the conditions mentioned in Table4. The assay substantially dropped down, the level of known and unknownimpurities increased and the colours of these salts changed from theoriginal white powders to yellow semi liquid products. Therefore,further study on these salts was not continued.

The 10, 20 and 32 days stability time points for the maleate, tosylate,HBr, and fumarate salts were continued in parallel to Bupropion HCl. Theresults are shown in FIGS. 3-10. The assay and impurity results for20-days in closed vials for these five salts were compared for salt plusexcipients and are presented FIGS. 3 and 4. FIGS. 5-7 show the resultsfor the drug salts (DS) kept for 32 days in closed vials and spiked withwater, water-isopropyl alcohol (IPA)-ethanol (EtOH) and IPA-EtOH.

In the closed vial assays, it is of note that the impurities (3-CBZ,852U77 & total) in the HBr salt were the lowest compared to all of theother salts including HCl (see FIG. 3). The levels of 852U77 in theother salts were comparable with HCl, however, the levels of 3-CBZ and,in particular levels of the total impurities were more with the othersalts than HCl. In the assay results (% potency), the tosylate and theHCl salts had similar potency after the days in a closed vial (FIG. 4).In the assay study, the order of stability for the bupropion salts wasas follows: HBr>HCl≈tosylate>fumarate>maleate).

The stability of the salts was then evaluated under more aggressiveconditions. The drug salts (DS) and excipients were spiked with water,water plus EtOH and IPA and EtOH and IPA. As can be seen from theresults shown in FIGS. 5-7, the order of stability (assay) of the saltscan be summarized as follows:

Stability with water: tosylate>maleate>HCl>HBr>fumarate.Stability with IPA & EtOH: HCl>HBr>tosylate>maleate>fumarate

Tosylate and maleate salts were more stable than other salts whenexposed directly to water, and less stable when exposed to the organicsolvents IPA & EtOH.

The HCl and HBr salts were more stable than other salts when exposeddirectly to IPA & EtOH and less stable with water. The fumarate salt wasneither stable in water nor in the organic solvents IPA & EtOH.

The level of the impurities (known, unknown & total) varied in each ofthe salts under the conditions of this experiment. The content of eachof the major impurities (3CBZ & 52U77) and the total impurities was asfollows (FIGS. 8-10): In water,

3-CBZ: HCl>HBr≈malcate≈fumarate

852U77: fumarate>HBr>maleate>HCl

Total imp. fumarate>HBr>HCl>tosylate>maleate

In IPA/EtOH:

3-CBZ: maleate>HBr>HCl>Fumarate

852U77: fumarate>HBr≈HCl≈maleate≈tosylate

Total imp. fumarate>maleate>HBr>HCl>tosylate

Based on the forced degradation stability studies conducted on the abovebupropion salts, the stability of oxalate, citrate, succinate andtartarate were shown to be very poor for the DS and the spiked DS (20days: discoloration, Low assay & high level of degradation impurities).The HBr, tosylate, maleate and to some extent fumarate salts are goodcandidates for further studies. Among the latter salts, HBr was the bestcandidate due to its superior stability in a closed container, lowestwater content, non-hygroscopic and its easy preparation.

The tosylate salt also showed good stability, although it was not aspure as the HBr, HCl or maleate. The tosylate salt, however, does nothave an acceptable toxicity profile.

It also was found that the presence of the organic solvents ethanol andisopropyl alcohol have significant impact on the stability of thesesalts.

Example 4 Comparative Forced Degradation Studies of Bupropion HCl andBupropion HBr API Salts

The stability of bupropion HCl and bupropion HBr API salts were furtherevaluated under the accelerated conditions of 40° C./75% RH in astability chamber. The samples were exposed to the above conditions in aclosed bottle for few days, and then subjected to HPLC analysis. Theamount of the main degradation products present after treatment werecompared with those amounts that were present initially.

Accurately quantities of each API were weighed individually in 50-mLamber glass bottles as shown in the Table 5. The bottles were closed andplaced in the stability chamber at 40° C./75% RH. The samples wereanalyzed after 14 and 24 days (study-1) and 10 days (study II), in aquantitative manner by direct treatment of the whole content of thebottle as per the HPLC standard test method (P05.901.10).

As shown in the Table 6, the resulting degradation products in bothbupropion HCl and bupropion HBr were either similar or better for theHBr salt.

The above study was repeated on two batches of each of the APIs for 10days. As shown in table 7, the level of impurities in the case ofbupropion HBr salt was lower than bupropion HCl, also the assay valuefor the latter was lower than that for the HBr salt.

Example 5 Bupropion HBr Extended Release (XL) Tablets

The aim of this example was to describe the development of bupropion HBrXL (174 and 348 mg). Granulation, tabletting and coating procedures areall described thoroughly in this example. In vitro testing was conductedon the cores, the EC coated cores and the final coated tablets in orderto determine which formulation gave the desired results.

From their structural formulae, it is observable that the differencebetween bupropion HCl and bupropion HBr is the salt. This, of course,results in a different molecular weight. However, these differences weretaken into account in the present study, and modifications were made inorder to obtain in vitro correlation results to the bupropion HCl usingdissolution studies.

It was previously observed that when 150 mg of bupropion HCl was testedfor its release of bupropion, the base value that was released was 130mg. However, when 150 mg of bupropion HBr was tested, the base valuereleased was only 112 mg. Thus, the amount of bupropion HBr had to beincreased in order to increase the base value from 112 mg to 130 mg,which was the target. Studies showed that 174 mg of bupropion HBr gave abase value release of 130 mg and is therefore why 174 mg was used asopposed to 150 mg bupropion HBr.

Bupropion HBr XL—Granulation Process

A summary of the manufacturing process used for the preparation ofbupropion HBr XL tablets is shown in FIG. 11.

The following materials were used in the granulation of the immediaterelease core of the bupropion HBr EA tablets: bupropion HBr, polyvinylalcohol (PVA) and purified water. Once granulated, lubricant (Compritol888) was added to complete the formulation.

Each Trial was divided into 5 parts. The percentage of API in eachformulation was 93.75%; the percentage of PVA in each formulation was3.125%. A summary of the breakdown of each trial per part is describedin Table 8.

The PVA was dissolved into the purified water using a magnetic stirrerand a clear colorless solution was made.

The NIRO Fluid Bed was used to granulate the bupropion HBr Granules withthe PVA solution in a process known as wet massing. FIG. 12 shows asummary of the granulation procedure.

The Bupropion HBr was loaded into the fluid bed and granulation wasinitiated. The specifications that were used as guidelines are listed inTable 9.

Loss on Drying was determined after each granulation using the MoistureAnalyzer. A 1 g sample was taken and loaded into the moisture analyzer.The sample ran for 5 minutes at a temperature of 105° C.

Upon completion of each batch part's granulation, the five parts werecombined together. They were hand screened using Mesh No. 14 (1.4 mm)and any oversized granulation was passed through the Comil fitted with a2 mm screen.

Compritol 888 was used as a lubricant in the formulation. The screenedbupropion HBr granules and the Compritol 888 were loaded into theV-blender and were blended for 5 minutes. The Compritol 888 made up3.125% of the formulation. The final granule batch size is described inTable 10.

Buproplon HBr XL—Tabletting Process

The Beta Press was used to compress the Bupropion HBr tablets. Dependingon the dose of the tablet, 174 mg or 348 mg, different tooling sets wereused. The 7 mm punches were used to compress the 174 mg tablets and 9 mmand 10 mm punches were used to compress the 348 mg tablets. Tooling waspolished prior to each run.

The tablet weights were determined as being 185.6 mg for the 174 mg dosetablets and 371.2 mg for the 348 mg dose tablets. These adjustments totablet weight were made in order to compensate for the fact thatbupropion HBr was being used in place of bupropion HCl. The individualtablet weights had a control limit of ±5%, and the average tablet weighthad a control limit of ±3% (using ten tablets).

A hardness tester was used to determine the load required todiametrically break the tablets (crushing strength) into two equalhalves. A predetermined range set the specifications for hardness, whichwas 6.0-12.0 SC for both the 174 mg and 348 mg tablets.

Friability was determined using tablets that equaled a weight of 6.5 gin a friability tester for 4 minutes at 25 rpm. Tablets were de-dustedbefore and after testing. A weight loss of less than 0.8% was used asthe criteria in order to accept or reject a batch.

Table 11 summarizes the specifications of the tablet press set-up. Allthe specifications were kept within the range and at the setting thatwas assigned, throughout all of the batches.

Table 12 summarizes the specifications that were kept constantthroughout the compression of all the batches.

The flow chart shown in FIG. 12 describes the steps that led up to andincluding the tabletting process. FIG. 13 shows a summary of thetabletting procedure.

Bupropion HBr XL—Coating Process

A summary of the coating process used for the coating of the BupropionHBr XL tablets is shown in FIG. 14. The first coat is an Ethocel coatthat controls the release, which is followed by a final coat that actsas a moisture barrier.

For the Ethocel coating and final coating of the Bupropion HBr XLtablets, the 15 inches O'Hara Labcoat II System was used. An attachedspraying nozzle and a propeller mixer were also used.

Several Ethocel coating solutions were developed and used to coat theBupropion HBr tablets. The Ethocel coating layer was placed on thetablets containing one of the formulations listed in Table 13.

In formulation 1, ethyl Alcohol 95% and IPA 99% were combined togetherin a stainless steel container. While stirring, PEG 4000 was added andallowed to dissolve. Once dissolved, Ethocel was added and left to stirfor 30 minutes. Then, Povidone was added to the solution and was mixedfor an overnight period (15-20 hours).

In formulation 2, PEG4000 was placed into a beaker with the DibutylSebacate and was stirred until it dissolved. Ethyl Alcohol 95% was addedaccordingly in order to allow the PEG 4000 to completely dissolve. In aseparate stainless steel container, the remaining Ethyl Alcohol 95% wasplaced and, while being stirred, Ethocel was added and stirred for 30minutes. Following that, Povidone was added and allowed to stir for anovernight period (15-20 hours).

In formulation 3, Ethyl Alcohol 95% was placed in a stainless steelcontainer. While stirring, PEG 4000 was added and allowed to dissolve.Once dissolved, Ethocel was added and left to stir for 30 minutes. Then,Povidone was added to the solution and was mixed for an overnight period(15-20 hours).

Two Final coating solutions were developed and used to coat theBupropion HBr tablets after they had been first coated with the Ethocelcoat.

One of the following formulations shown in Table 14 was used to coat thetablets with a final coat.

In Formulation A, the purified water was placed in a glass beaker andChroma-Tone DEB 5156-CLE was added and allowed to mix for 15 minutes.The Eudragit was passed through a Mesh screen (no. 60) prior to use.Following this, the Eudragit was added to the beaker and was stirred for15 more minutes.

In Formulation B, part 1 of the Purified Water was placed into a glassbeaker and PEG 4000 was added to it and allowed to mix until it wascompletely dissolved (5 minutes). The Triethyl Citrate was then addedand left to mix for another 5 minutes. Once dissolved, the solution wasthen added to the Eudragit Suspension and left to stir for 45 minutes.The Eudragit was passed through a Mesh screen (no. 60) prior to use. Ina separate beaker, part 2 of the purified water was added to the Syloid244FP and mixed until it was completely dissolved (10 minutes). Finallythe Syloid Suspension was added to the Eudragit Suspension and left tostir for another 10 minutes.

Table 15 summarizes the specifications that were monitored in theEthocel coating process and their ranges.

Table 16 summarizes the specifications that were monitored in the finalcoating process and their ranges.

In-Vitro Studies on the Bupropion HBr Cores

Dissolution was performed on the Bupropion HBr cores, on the differentweight gains of Ethocel coated cores and on the different weight gainsof final coated tablets. USP-1 method was used to conduct these studies.The dissolution test was performed using 900 mL of 0.1N HCl and at aspeed of 75 rpm. Samples were taken at every hour for 16 hours. Thedissolution profiles were obtained by plotting the cumulative percent ofAPI dissolved against sampling time points. Sink conditions weremaintained throughout all the experiments.

On several trials, USP-3 method was used to conduct the dissolutionstudies. These dissolution tests were performed for 16 hours total withthe following breakdown: 2 hours using 900 mL of Simulated Gastric Fluid(SGF) at pH 1.2 with 0.5% of Sodium Lauryl Sulfate (SLS), followed by 2hours in 900 mL of Acetate Buffer at a pH of 4.5, followed by 12 hoursin 900 mL of Phosphate Buffer Simulated Intestinal Fluid (SIF) at a pHof 6.8. These results were plotted with the in-vivo data and theBupropion HCl data in order for a comparison to be made.

Study on Batch BUP-HBr-XL-009-5

The formulation was granulated using NIRO Fluid Bed. After granulationwas completed, the batch was screened and then prior to compression thelubricant (Compritol 888) was added. The final blend was compressed into348 mg tablets using the Beta press with 9 mm and 10 mm standard, round,concave tooling. Table 17 describes the amounts of each material in thegranulation of the 348 mg tablets. A first compression run was done toproduce tablets with different hardness values so as to determine theeffects of hardness, if any, on the dissolution (FIG. 15). Dissolutionwas conducted on the 348 mg cores in order to determine their release(FIG. 16).

The granulation results show that the average granulation time is 2.0hours and the average LOD % is 0.345%. Tables 18 and 19 summarize thetheoretical and actual values of the parameters that were monitored inthe compression process using the 9 mm and 10 mm tooling, respectively.

In order to determine the tablet hardness for this study, tablets ofdifferent hardness values were compressed and dissolution was conductedon them to see the difference.

Tablets with a hardness of 4 kp, 6-7 kp and 9-10 kp were compressed andthe dissolution profiles of each were shown in FIG. 15. It was observedthat there was no significant difference between the three differenthardness ranges.

The dissolution profiles of the 348 mg (FIG. 16) and 174 mg cores (FIG.17) showed that the cores were releasing approximately 100 percent ofAPI in an hour.

Dissolution of the 10 mm, 348 mg cores was done also in order to see ifthese tablets released faster when compared to the 9 mm cores due totheir larger surface area (FIG. 17).

When the dissolution results of the 9 mm and 10 mm cores were compared(FIG. 18), the 10 mm cores showed no difference from the 9 mm cores.Thus, the 10 mm cores were no longer manufactured or used in this study.

Study on Batch BUP-HBr-XL-021-5

The Formulation was granulated using NIRO Fluid Bed. The final blend wascompressed into 174 mg tablets using the Beta press with 7 mm standard,round, concave, stainless steel tooling. Table 20 describes the amountsof each material in the granulation of the 174 mg tablets. It was notedthat the 348 and the 174 mg tablets had the same composition and amountsof each material; the only variation was the tablet weight, which wasadjusted at the compression stage. Dissolution was conducted on the 174mg cores in order to see their release (FIG. 19).

The granulation results show that the granulation time is 2 hours 6minutes and the average LOD % is 0.26%. Table 21 summarizes thetheoretical and actual values of the parameters that were monitored inthe compression process using the 7 mm tooling.

The dissolution profile of the 174 mg (FIG. 19) showed that the coreswere releasing approximately 100 percent of API in an hour.

Study on Batch BUP-HBr-XZ-348 mg-013-5

Using 348 mg tablets, an Ethocel coating followed by a Final coating,were sprayed onto the tablets using the O'Hara Labcoat II CoatingEquipment.

The materials used in the Ethocel (EC) coating, their percentcontribution to the total solution, the amounts of each in the batch andthe percentage of the solids in the solution were all listed in Table22.

The parameters are as follows: Spray Rate: 13 g/min; Pan Speed: 12.0rpm; Inlet Air: 50° C.; Product Temperature: 35° C.±5° C.; and SupplyAir Flow: 200 CFW.

It took 2 hours and 25 minutes to coat the tablets with a weight gain of32 mg. Tablet weights were taken and recorded in Table 23 at 28 mg, 30mg, 32 mg, and 34 mg weight gains.

The dissolution profile (FIG. 20) shows that the tablets with the 34 mgweight gain of EC coating released Bupropion HBr the slowest whencompared to the others and that the tablets with the 28 mg weight gainreleased Bupropion HBr the fastest when compared to the other weightgains.

The materials used in the final coating, their percent contribution tothe total solution, the amounts of each in the batch, the amount ofsolid contribution in grams and the percentage of the solids in thesolution were all listed in Table 24.

The parameters are as follows: Spray Rate: 6 g/min; Pan Speed: 12.0 rpm;Inlet Air: 40° C.; Product Temperature: 35° C.±5° C.; and Supply AirFlow: 200 CFW.

After this trial run, Chroma-Tone was no longer used due to theformulation problems it caused. First, it limited the composition of theformulation due to its inflexibility, as Syloid, PEG and TriethylCitrate ratios could not be varied. Second, the solution foamed andcoagulated, which in turn caused the process for making the coatingsolution to be changed from the original so that it did notre-coagulate. Chroma-Tone can, however, still be considered an optionfor the formulation but different grades and mixtures would need to beused and made in order to accommodate the Bupropion HBr XL tablets.

It took 31 minutes to add a 7 mg weight gain of the final coatingsolution to the tablets.

Tablet weights were taken and recorded in Table 25 at 4 mg, 5 mg, 6 mgand 7 mg weight gains.

The dissolution profile (FIG. 21) shows that the tablets with the 7 mgweight gain of Final coating released the slowest when compared to theother two weight gains (5 mg and 6 mg weight gains).

Study on Batch BUP-HBr-XL-348 mg-018-5

Using 348 mg tablets, an Ethocel coating followed by a final coating,were sprayed onto the tablets using the O'Hara Labcoat II CoatingEquipment.

The materials used in the Ethocel (EC) coating, their percentcontribution to the total solution, the amounts of each in the batch andthe percentage of the solids in the solution were all listed in Table26.

The parameters are as follows: Spray Rate: 13 g/min; Pan Speed: 12.0rpm; Inlet Air: 50° C.; Product Temperature: 35° C.±5° C.; and SupplyAir Flow: 200 CFW.

The coating process of this trial took 2 hours and 13 minutes to obtaina 32 mg weight gain. Tablet weights were taken and recorded in Table 27at 26 mg, 28 mg, 30 mg, and 32 mg weight gains.

FIG. 22 shows that the tablets with the 30 mg and 32 mg weight gain ofEC coating solution released at almost the same rate. The tablets withthe 32 mg weight gain released slower than the tablets with the 30 mgweight gain in the first 5 hours of dissolution. After 6 hours, thetablets with the 32 mg weight gain released slightly faster than thosewith a 30 mg weight gain. The f2 similarity factor confirmed that therelease rate of both weight gains was similar (91.32%).

The materials used in the final coating, their percent contribution tothe total solution, the amounts of each in the batch, the amount ofsolid contribution in grams and the percentage of the solids in thesolution were all listed in Table 28.

The parameters are as follows: Spray Rate: 6 g/min; Pan Speed: 12.0 rpm;Inlet Air: 40° C.; Product Temperature: 35° C.±5° C.; and Supply AirFlow: 200 CFW.

It took 41 minutes to add a 7 mg weight gain of the final coatingsolution to the tablets. Tablet weights were taken and recorded in Table29 at 4 mg, 5 mg, 6 mg, and 7 mg weight gains.

FIG. 23 shows the release profile of the tablets with the 7 mg weightgain of Final coating.

Study on Batch BUP-HBr-XL-174 mg-022-5

Using 174 mg tablets, an Ethocel coating followed by a final coating,were sprayed onto the tablets using the O'Hara Labcoat II CoatingEquipment.

The materials used in the Ethocel (EC) coating, their percentcontribution to the total solution, the amounts of each in the batch andthe percentage of the solids in the solution were all listed in Table30.

The parameters are as follows: Spray Rate: 13 g/min; Pan Speed: 12.0rpm; Inlet Air: 50° C.; Product Temperature: 35° C.±5° C.; and SupplyAir Flow: 200 CFW.

It took 4 hours and 30 minutes to add a 30 mg weight gain of the ECcoating solution to the tablets. Tablet weights were taken at 20 mg, 22mg, 24 mg, 26 mg, 28 mg, 29 mg, and 30 mg weight gains and were recordedin Table 31.

FIG. 24 shows the % dissolved of each of the samples with differentweight gains of EC coating (22 mg, 24 mg, 28 mg and 30 mg weight gains).From the graph, it was evident that the tablets with the 30 mg weightgain of EC coating released slower than the other weight gains. When therelease rates of the tablets with the 30 mg and the 28 mg weight gainswere compared, there was only a slight difference noticed in therelease. The f2 similarity factor confirmed the similarity of the tworeleases (92.34%).

The materials used in the final coating, their percent contribution tothe total solution, the amounts of each in the batch, the amount ofsolid contribution in grams and the percentage of the solids in thesolution were all listed in Table 32.

The parameters are as follows: Spray Rate: 6 g/min; Pan Speed: 12.0 rpm;Inlet Air: 40° C.; Product Temperature: 35° C.±5° C.; and Supply AirFlow: 200 CFW.

It took 1 hour and 26 minutes to add a 7 mg weight gain of the finalcoating solution to the tablets. Tablet weights were taken and recordedin Table 33 at 4 mg, 5 mg, 6 mg, and 7 mg weight gains.

The dissolution profile (FIG. 25) shows that the tablets with the 7 mgweight gain of final coating released the slowest, in comparison to the5 mg and the 6 mg weight gains.

Study on Batch BUP-HBr-XL-348 mg-023-5

Using 348 mg tablets, an Ethocel coating was sprayed onto the tabletsusing the O'Hara Labcoat II Coating Equipment.

The materials used in the Ethocel (EC) coating, their percentcontribution to the total solution, the amounts of each in the batch andthe percentage of the solids in the solution were all listed in Table34.

The parameters are as follows: Spray Rate: 13 g/min; Pan Speed: 12.0rpm; Inlet Air: 50° C.; Product Temperature: 35° C.±5° C.; and SupplyAir Flow: 200 CFW.

It took 2 hours and 16 minutes to add a 32 mg weight gain of the ECcoating solution to the tablets. Tablet weights were taken at 26 mg, 28mg, 30 mg, and 32 mg weight gains and were recorded in Table 35.

The dissolution profile (FIG. 26) shows that the tablets with the 32 mgweight gain of EC coating, when compared to the tablets with the 26 mg,28 mg and the 30 mg weight gain of EC coating, released at the slowestrate.

Study on Batch BUP-HBr-XL-348 mg-025-5

Using 348 mg tablets, an Ethocel coating followed by a final coating,were sprayed onto the tablets using the O'Hara Labcoat II CoatingEquipment.

The materials used in the Ethocel (EC) coating, their percentcontribution to the total solution, the amounts of each in the batch andthe percentage of the solids in the solution were all listed in Table36.

The parameters are as follows: Spray Rate: 13 g/min; Pan Speed: 12.0rpm; Inlet Air: 50° C.; Product Temperature: 35° C.±5° C.; and SupplyAir Flow: 200 CFW.

It took 2 hours and 13 minutes to add a 32 mg weight gain of the ECcoating solution to the tablets. Tablet weights were taken at 26 mg, 28mg, 30 mg, and 32 mg weight gains and were recorded in Table 37.

The dissolution profile (FIG. 27) shows that the tablets with the 32 mgweight gain of EC coating when compared to those with 26 mg weight gainreleased slower in the beginning and then faster after 7 hours. Whencomparing the tablets with 32 mg weight gain of EC coating to those with30 mg weight gain of EC coating, the tablets with the 32 mg weight gainreleased slower up until 10 hours. The f2 similarity factor showed thatthe release of the tablets with the 30 mg and 32 mg weight gains were infact similar (93.72%).

The materials used in the final coating, their percent contribution tothe total solution, the amounts of each in the batch, the amount ofsolid contribution in grams and the percentage of the solids in thesolution were all listed in Table 38.

The parameters are as follows: Spray Rate: 6 g/min; Pan Speed: 12.0 rpm;Inlet Air: 40° C.; Product Temperature: 35° C.±5° C.; and Supply AirFlow: 200 CFW.

The coating solution was altered for this batch by changing thepercentage of solid from each of the solid components in the solution.The percentage of Eudragit solid contribution was decreased from 65% to56.5%. The percentage of Syloid, Carbowax and Triethyl Citrate wereincreased from 25%, 6.65% and 3.39% to 30%, 9% and 4.5%, respectively.

It took 40 minutes to add a 7 mg weight gain of the final coatingsolution to the tablets. Tablet weights were taken and recorded (Table39) at 4 mg, 5 mg, 6 mg, and 7 mg weight gains.

The dissolution profile (FIG. 28) shows that the tablets with the 7 mgweight gains released the slowest of the three samples tested. However,f2 calculation showed that the tablets with the 6 mg weight gainreleased similarly to those with the 7 mg weight gain of Final coating(93.33%).

Study on Batch BUP-HBr-XL-348 mg-026-5

Using 348 mg tablets, an Ethocel coating was sprayed onto the tabletsusing the O'Hara Labcoat II Coating Equipment.

The materials used in the Ethocel (EC) coating, their percentcontribution to the total solution, the amounts of each in the batch andthe percentage of the solids in the solution were all listed in Table40.

The parameters are as follows: Spray Rate: 13 g/min; Pan Speed: 12.0rpm; Inlet Air: 50° C.; Product Temperature: 35° C.±5° C.; and SupplyAir Flow: 200 CFW.

It took 2 hours and 11 minutes to add a 32 mg weight gain of the ECcoating solution to the tablets. Tablet weights were taken at 26 mg, 28mg, 30 mg, and 32 mg weight gains and were recorded in Table 41.

The dissolution profile (FIG. 29) shows that the tablets with the 32 mgweight gain of EC coating released the slowest when compared to theother three samples with lower weight gains of EC coating (26 mg, 28 mgand 30 mg).

Study on Batch BUP-HBr-XL-174 mg-027-5

Using 174 mg tablets, an Ethocel coating followed by a final coating,were sprayed onto the tablets using the O'Hara Labcoat II CoatingEquipment.

The materials used in the Ethocel (EC) coating, their percentcontribution to the total solution, the amounts of each in the batch andthe percentage of the solids in the solution were all listed in Table42.

The parameters are as follows: Spray Rate: 13 g/min; Pan Speed: 12.0rpm; Inlet Air: 50° C.; Product Temperature: 35° C.±5° C.; and SupplyAir Flow: 200 CFW.

It took 3 hours and 29 minutes to add a 32 mg weight gain of the ECcoating solution to the tablets. Tablet weights were taken at 22 mg, 24mg, and 26 mg weight gains and were recorded in Table 43.

The dissolution profile (FIG. 30) shows that the tablets with the 26 mgweight gain of EC coating released the slowest of the three samplestested.

The materials used in the final coating, their percent contribution tothe total solution, the amounts in each in the batch, the amount ofsolid contribution in grams and the percentage of the solids in thesolution were all listed in Table 44.

The parameters are as follows: Spray Rate: 6 g/min; Pan Speed: 12.0 rpm;Inlet Air: 40° C.; Product Temperature: 35° C.±5° C.; and Supply AirFlow: 200 CFW.

It took 1 hour and 17 minutes to add a 7 mg weight gain of the finalcoating solution to the tablets. Tablet weights were taken and recordedin Table 45 at 4 mg, 5 mg, 6 mg, and 7 mg weight gains.

The dissolution profile (FIG. 31) shows that the tablets with the 7 mgweight gain of final coating initially released slower that the tabletswith 4 mg, 5 mg and 6 mg weight gains. However, at approximately 12hours, all 4 samples were releasing similarly.

Example 6 Buproprion HBr Enhanced Absorption (Ea) Tablets

This example describes the development of bupropion EA “EnhancedAbsorption” tablets (150 mg and 300 mg). Granulation, tabletting andcoating procedures are all described thoroughly in this example. Invitro testing was conducted on the EC coated cores in order to determinewhich formulation gave the desired results.

Bupropion HBr was used in this study and its only difference toBupropion HCl is the salt. A major advantage of an enhanced absorptioncomposition can be lessening the amount of drug in the composition,which in turn can lead to a reduction of side effects.

The overall process for the development of bupropion HBr EA tablets isshown in FIG. 32.

Bupropion HBr EA—Granulation Process

A summary of the granulation process of the bupropion HBr EA tablets isshown in FIG. 33.

The following materials were used in the granulation of the immediaterelease core of the bupropion HBr EA tablets: bupropion HBr, polyvinylalcohol and purified water. Once granulated, lubricant (Compritol 888)was added to complete the formulation. It must be noted that thegranulation procedure for the bupropion HBr XL and Bupropion HBr EA arethe same.

Each trial was divided into 5 parts. The percentage of API in eachformulation was 93.75% and the percentage of PVA in each formulation was3.125%. A summary of the breakdown of each trial per part was describedin Table 46.

The Polyvinyl Alcohol was dissolved into the purified water using amagnetic stirrer and a clear colourless solution was made.

The NIRO Fluid Bed was used to granulate the Bupropion HBr Granules withthe PVA solution in a process known as wet massing.

The Bupropion HBr was loaded into the fluid bed and granulation wasinitiated. The specifications that were used as guidelines were listedin Table 47.

Loss on Drying was determined after each granulation using the MoistureAnalyzer. A 1 g sample was taken and loaded into the moisture analyzer.The sample ran for 5 minutes at a temperature of 105° C.

Upon completion of each batch part's granulation, the five parts werecombined together. They were hand screened using Mesh No. 14 (1.4 mm)and any oversized granulation was passed through the Comil fitted with a2 mm screen.

Compritol 888 was used as a lubricant in the formulation. The screenedBupropion HBr granules and the Compritol 888 were loaded into theV-blender and were blended for 5 minutes. The Compritol 888 made up3.125% of the formulation. The final granule batch size was described inTable 48.

Bupropion HBr EA—Tabletting Process

The Beta Press was used to compress the Bupropion HBr tablets. Dependingon the dose of the tablet, 150 mg or 300 mg, different tooling sets wereused. The 7 mm punches were used to compress the 150 mg tablets and 9 mmpunches were used to compress the 300 mg tablets. Tooling was polishedprior to each run.

The tablet weights were determined as being 160.0 mg for the 150 mg dosetablets and 320.0 mg for the 300 mg dose tablets. These adjustments totablet weight were made in order to compensate for the fact thatbupropion HBr was being used in place of bupropion HCl. Priorinvestigations showed that bupropion HBr tablets with the above statedweights gave in vitro results similar to those of the 150 mg and 300 mgbupropion HCl tablets. The individual tablet weights had a control limitof ±5%, and the average tablet weight had a control limit of ±3% (usingten tablets).

A hardness tester was used to determine the load required todiametrically break the tablets (crushing strength) into two equalhalves. A predetermined range set the specifications for hardness, whichwas 6.0-12.0 SC for both the 174 mg and 348 mg tablets.

Friability was determined using tablets that equaled a weight of 6.5 gin a friability tester for 4 minutes at 25 rpm. Tablets were de-dustedbefore and after testing. A weight loss of less than 0.8% was used asthe criteria in order to accept or reject a batch.

Table 49 summarizes the specifications of the tablet press set-up. Allthe specifications were kept within the range and at the setting thatwas assigned, throughout all of the batches.

Table 50 summarizes the specifications that were kept constantthroughout the compression of all the batches.

Bupropion HBr EA—Coating Process

A summary of the coating process of the 150 mg and 300 mg bupropion HBrEA tablets with an Ethocel Coating is shown in FIG. 35.

For the Ethocel coating of the Bupropion HBr EA tablets, the 15 inchesO'Hara Labcoat II System was used. An attached spraying nozzle and apropeller mixer were also used.

Several Ethocel coating solutions were developed and used to coat theBupropion HBr tablets. An Ethocel coating layer was placed on thetablets containing one of the formulations listed in Table 51.

In formulation 1, Ethyl Alcohol 200 proof was weighed out in a stainlesssteel container. While stirring, PEG 4000 was added and allowed todissolve. Once dissolved, Ethocel was added and left to stir for 30minutes. Then, Povidone was added to the solution and was mixed for anovernight period (15-20 hours).

In formulation 2, PEG4000 was placed into a beaker with the DibutylSebacate and was stirred until it dissolved. This was added to the EthylAlcohol 200 proof that had already been weighed out in a stainless steelcontainer. Following this, Ethocel was added and stirred for 30 minutes.Thereafter, Povidone was added and allowed to stir for an overnightperiod (15-20 hours).

In formulation 3, Ethyl Alcohol 200 proof was placed in a stainlesssteel container. While stirring, Dibutyl Sebacate was added and allowedto dissolve. Once dissolved, Ethocel was added and left to stir for 30minutes. Then, Povidone was added to the solution and was mixed for anovernight period (15-20 hours).

In formulation 4, Ethyl Alcohol 95% USP was weighed out in a stainlesssteel container. While stirring, PEG 4000 was added and allowed todissolve. Once dissolved, Ethocel was added and left to stir for 30minutes. Then, Povidone was added to the solution and was mixed for anovernight period (15-20 hours).

Table 52 summarizes the specifications that were monitored in thecoating process and their ranges.

In-Vitro Studies on the Bupropion HBr Cores

Dissolution was performed on the Bupropion HBr cores and on thedifferent weight gains of Ethocel coated cores. USP-1 method was used toconduct these studies. The dissolution test was performed using 900 mLof 0.1N HCl and at a speed of 75 rpm. Samples were taken at every hourfor 16 hours. The dissolution profiles were obtained by plotting thecumulative percent of API dissolved against sampling time points. Sinkconditions were maintained throughout all the experiments.

On several trials, USP-3 method was used to conduct the dissolutionstudies. These dissolution tests were performed for 16 hours total withthe following breakdown: 2 hours using 900 mL of Simulated Gastric Fluid(SGF) at pH 1.2 with 0.5% of Sodium Lauryl Sulfate (SLS), followed by 2hours in 900 mL of Acetate Buffer at a pH of 4.5, followed byl 2 hoursin 900 mL of Phosphate Buffer Simulated Intestinal Fluid (SIF) at a pHof 6.8. These results were plotted with the in-vitro data and theBupropion HCl data in order for a comparison to be made.

Study on Batch BUP-HBr-XL-016-5

The formulation was granulated using NIRO Fluid Bed. The final blend wascompressed into 300 mg tablets using the Beta press with 9 mm round,concave tooling and into 150 mg tablets with 7 mm round, concavetooling. Table 53 describes the amounts of each material in thegranulation of the 300 mg tablets and Table 54 describes the amounts forthe 150 mg tablets. It was noted that they were the same; the onlyvariation was the tablet weight, which was adjusted at the compressionstage. A first compression run was done to produce tablets withdifferent hardness values so as to determine the effects of hardness, ifany, on the dissolution (FIG. 36). Dissolution was conducted on the 300mg and 150 mg cores in order to determine their release (FIGS. 37 and38, respectively). After granulation was completed, the batch wasscreened and then prior to compression, the lubricant (Compritol 888)was added.

The granulation results show that the average granulation time is 2.0hours and the average LOD % is 0.342%. Table 55 and Table 56 summarizethe theoretical and actual values of the parameters that were monitoredin the compression process using the 9 mm and 7 mm tooling respectively.

FIG. 36 shows that the different hardness ranges did not drasticallyaffect the dissolution profiles. The dissolution profiles of the 300 mg(FIG. 37) and 150 mg cores (FIG. 38) show that the cores were releasingapproximately 100 percent of API in an hour.

Study on Batch BUP-HBr-EA-300 mg-001-5

Using 300 mg Bupropion HBr core tablets, an Ethocel coating was sprayedonto the tablets using the O'Hara Labcoat II Coating Equipment.

The materials used in the Ethocel (EC) coating, their percentcontribution to the total solution, the amounts of each in the batch andthe percentage of the solids in the solution were all listed in Table57.

The parameters are as follows: Spray Rate: 14 g/min; Pan Speed: 12.0rpm; Inlet Air: 50° C.; Product Temperature: 35° C.±2° C.; and SupplyAir Flow: 200 CFW.

It took 4 hours and 4 minutes to coat the tablets with a weight gain of54 mg. Tablet weights were taken and recorded in Table 58 at 44 mg, 46mg, 48 mg, 50 mg 52 mg, and 54 mg weight gains.

The dissolution profile (FIG. 39) shows that the tablets with the 44 mgweight gain released the fastest and the tablets with the 54 mg weightgain released the slowest from the 6 different weight gains that weretested.

Dissolution using USP3 was also conducted on this trial, using thetablet with the 52 mg weight gain. The dissolution profile was plottedas time in hours versus % Dissolved, and was plotted alongside the invivo data and the Bupropion HCl data in order for a comparison to bemade. The results (FIG. 40) showed that the trial did not match the invivo data, nor did it match the Bupropion HCl data.

Study on Batch BUP-HBr-EA-150 mg-002-5

Using 150 mg tablets, an Ethocel coating was sprayed onto the tabletsusing the O'Hara Labcoat II Coating Equipment.

The materials used in the Ethocel (EC) coating, their percentcontribution to the total solution, the amounts of each in the batch andthe percentage of the solids in the solution were all listed in Table59.

The parameters are as follows: Spray Rate: 14 g/min; Pan Speed: 12.0rpm; Inlet Air: 50° C.; Product Temperature: 35° C.±2° C.; and SupplyAir Flow: 200 CFW.

The coating process of this trial took 4 hours and 38 minutes to obtaina 36 mg weight gain. Tablet weights were taken and recorded in Table 60at 18 mg, 20 mg, 22 mg, 24 mg, 26 mg, 28 mg, 30 mg, 32 mg, 34 mg and 36mg weight gains.

The dissolution profile (FIG. 41) shows that the tablets with the 18 mgand 20 mg weight gains of EC coating released the fastest of all theweight gains tested. It was the tablets with the 36 mg weight gain thatreleased the slowest when compared to all the other weight gains.

Study on Batch BUP-HBr-EA-300 mg-003-5

Using 300 mg tablets, an Ethocel coating was sprayed onto the tabletsusing the O'Hara Labcoat II Coating Equipment.

The materials used in the Ethocel (EC) coating, their percentcontribution to the total solution, the amounts of each in the batch andthe percentage of the solids in the solution were all listed in Table61.

The parameters are as follows: Spray Rate: 14 g/min; Pan Speed: 12.0rpm; Inlet Air: 50° C.; Product Temperature: 35° C.±2° C.; and SupplyAir Flow: 200 CFW.

It took 4 hours and 13 minutes to add a 54 mg weight gain of the ECcoating solution to the tablets. Tablet weights were taken at 44 mg, 46mg, 48 mg, 50 mg, 52 mg, and 54 mg weight gains and were recorded inTable 62.

The dissolution profile (FIG. 42) shows that the tablets with the 52 mgweight gain of EC coating released the slowest when compared to theother profiles with different weight gains.

Study on Batch BUP-HBr-EA-300 mg-004-5

Using 300 mg tablets, an Ethocel coating was sprayed onto the tabletsusing the O'Hara Labcoat II Coating Equipment.

The materials used in the Ethocel (EC) coating, their percentcontribution to the total solution, the amounts of each in the batch andthe percentage of the solids in the solution were all listed in Table63.

The parameters are as follows: Spray Rate: 14 g/min; Pan Speed: 12.0rpm; Inlet Air: 50° C.; Product Temperature: 35° C.±2° C.; and SupplyAir Flow: 200 CFW.

It took 4 hours and 13 minutes to add a 54 mg weight gain of the ECcoating solution to the tablets. Tablet weights were taken at 44 mg, 46mg, 48 mg, 50 mg, 52 mg, and 54 mg weight gains and were recorded inTable 64.

The dissolution profile (FIG. 43) shows that the tablets with the 52 mgweight gain released the slowest when compared to the other profile andthe tablets with the 44 mg weight gain of EC coating released thefastest.

Study on Batch BUP-HBr-EA-300 mg-005-5

Using 300 mg tablets, an Ethocel coating was sprayed onto the tabletsusing the O'Hara Labcoat II Coating Equipment.

The materials used in the Ethocel (EC) coating, their percentcontribution to the total solution, the amounts of each in the batch andthe percentage of the solids in the solution were all listed in Table65.

The parameters are as follows: Spray Rate: 14 g/min; Pan Speed: 12.0rpm; Inlet Air: 50° C.; Product Temperature: 35° C.±2° C.; and SupplyAir Flow: 200 CFW.

It took 4 hours and 14 minutes to add a 54 mg weight gain of the ECcoating solution to the tablets. Tablet weights were taken at 44 mg, 46mg, 48 mg, 50 mg, 52 mg, and 54 mg weight gains and were recorded inTable 66.

FIG. 44 shows that the tablets with the 54 mg weight gain released theslowest when compared to the other profiles and that the tablets withthe 44 mg weight gain of EC coating released the fastest of the sixprofiles.

Study on Batch BUP-HBr-EA-150 mg-006-5

Using 150 mg tablets, an Ethocel coating was sprayed onto the tabletsusing the O'Hara Labcoat II Coating Equipment.

The materials used in the Ethocel (EC) coating, their percentcontribution to the total solution, the amounts of each in the batch andthe percentage of the solids in the solution were all listed in Table67.

The parameters are as follows: Spray Rate: 14 g/min; Pan Speed: 12.0rpm; Inlet Air: 50° C.; Product Temperature: 35° C.±2° C.; and SupplyAir Flow: 200 CFW.

The coating process of this trial took 4 hours and 36 minutes to obtaina 36 mg weight gain. Tablet weights were taken and recorded in Table 68at 18 mg, 20 mg, 22 mg, 24 mg, 26 mg, 28 mg, 30 mg, 32 mg, 34 mg and 36mg weight gains.

The dissolution profile (FIG. 45) shows that the tablets with the 36 mgweight gain of EC coating released the slowest when compared to theother four profiles (24 mg, 28 mg, 32 mg and 34 mg weight gains).

Dissolution using USP3 was also conducted with this trial, in order tosee if the results were close to the in vivo data and the in vitro dataof the Bupropion HCl 300 mg target. The dissolution profile (FIG. 46)shows that the 150 mg Bupropion HBr EA tablets with 24 mg weight gainwas close to the in vivo profile.

Study on Batch BUP-HBr-EA-150 mg-007-5

Using 150 mg tablets, an Ethocel coating was sprayed onto the tabletsusing the O'Hara Labcoat II Coating Equipment.

The materials used in the Ethocel (EC) coating, their percentcontribution to the total solution, the amounts of each in the batch andthe percentage of the solids in the solution were all listed in Table69.

Example 7 Comparative Forced Degradation Studies on Bupropion HCl andBupropion HBr Drug Products

The Bupropion HCl and HBr tablets (EC coated and the EC+moisture barriercoated) were placed individually on an open dish, and exposed to theaccelerated conditions of 40° C./75% RH in the stability chamber. After13 and 20 days, the samples were assayed and impurity analysis wasperformed as per the method HPLC P05.901.10.

Table 70 and FIG. 47 show the 13 and 20 days results of the forceddegradation study on both Bupropion HCl and HBr EC coated tablets. Forthe Bupropion HCl product, the main degradation impurities 3-CBZ and852U77 were 0.12% and 0.38% respectively, whereas, for the BupropionHBr, these values were 0.07% and 0.49% respectively. The otherdegradation impurities and the total unknowns were very similar for bothproducts; however, the assay value for the HBr product was higher thanthe HCl. The difference in the assay and the impurity levels were moresignificant in the final drug products. As shown in the Table 71 andFIG. 48, for the same period of the study the assay of the Bupropion HClwas lower (95.5%) and the level of the degradation and total unknownswere higher (3-CBZ: 0.28%, 852U77: 1.23%, 827U76: 0.10% and total 1.73%)than the Bupropion HBr (3-CBZ: 0.12%, 852U77: 0.41%, 827U76: 0.05% andtotal 0.75%).

Example 8 Further Forced Degradation Studies on Bupropion HBr andBupropion HCl in the Presence of Excipients

Further forced degradation studies were carried out at 55° C., at 55° C.and 100% relative humidity, at 100° C., and at 105° C. on both the HCland HBr Bupropion salts in the presence of excipients. The averageweight of the excipients and the weight of the active pharmaceuticalingredient (API) present in the samples are presented in Table 72. Theresults from this study are presented in FIGS. 49-53. FIG. 49 shows theamount of 3-CBA impurity in the various samples. FIG. 50 shows theamount of 852U77 impurity in the various samples. FIG. 51 shows theamount of 20U78 impurity in the various samples. FIG. 52 shows theamount of 827U76 impurity in the various samples. FIG. 53 is a graphshowing the loss of each salt over time in a TGA experiment at 100° C.These results indicate that at elevated temperatures, adisproportionation of the HCl salt occurs with concomitant loss ofgaseous HCl. This disproportionation did not occur with the HBr salt.

It is clear from the results that bupropion HBr shows significantimprovements in stability compared to bupropion HCl. The degradation ofbupropion HBr was slower as indicated by the formation of less amountsof impurities compared to bupropion HCl.

Example 9 Preparation of Further Bupropion HBr EA Tablets

Using procedures as described in Example 6, further bupropion EA tabletswere prepared using the quantities listed in Table 73.

Example 10 Accelerated Stability Study of Bupropion HBr

The stability of bupropion HBr was evaluated under the acceleratedconditions of 40° C.+2° C. and 75%+5% RH in a stability chamber. Thesamples were prepared in closed bottles and placed in the stabilitychamber. HPLC analysis was conducted on the samples prior to placingthem in the stability chamber (time 0), and after 3 months and 6 months.The amounts of the main degradation products present at time 0 werecompared with those amounts present after 3 months and 6 months. Asshown in Table 74-76 three different batches of bupropion HBr weretested. For each sample tested, at each time period, two different HPLCassays were run. The first assay labeled chromatographic purity A,measured the percentage of three impurities 3′chloropropiophenone,3′-Chloro-2-bromopropiophenone and 3′-Chlorobenzoic acid. The secondassay, labeled chromatographic purity B, measured the percentage of2-N-(tert-Butyl)-aminopropiophenone, a single unknown impurity and thetotal unknown impurities. Finally a total percentage of impurities(known and unknown) was reported for each sample. From the datapresented it can be seen that there is a slight increase in the impurity3′-chloropropiophenone. While slight fluctuations were seen in thepercentage of other impurities there was no trend showing an increase ofthese impurities at the 3- and 6-month time periods as measured. Thetotal percentage of impurities for each of the HBr samples did notchange at either the 3-month or the 6-month time periods. These resultsindicate that the HBr salt of bupropion was highly stable under theaccelerated stability test conditions.

Example 11 Shelf Life Stability Program

The stability of bupropion HBr was studied over a longer term underconditions meant to approximate standard storage or shelf conditions.Samples were prepared in closed containers and subjected to long-termstorage at 25° C.+2° C. and 60%+5% RH in a stability chamber. Thesamples were analyzed by HPLC prior to being placed in the stabilitychamber (time 0) and after 3 months and 6 months. The amounts of themain degradation products present at time 0 were compared with theamounts present at 3 months and 6 months. As shown in Table 77-79 threedifferent batches of bupropion HBr were tested. As in Example 10 eachsample was tested under two HPLC assay conditions to identify 6impurities or groups of impurities as described in Example 10. From theresults shown in tables 77-79 it can be seen that the percentage of theimpurity 3′-chloropropiophenone increased slightly over time. While theother impurities fluctuated slightly they did not show an increasingtrend over time. These results demonstrate the stability of bupropionHBr under standard shelf conditions over an extended period of time.

Example 12 Preparation and Stability Study of Bupropion HBr PolymorphicForms I, II and III

Bupropion hydrobromide polymorphic forms I, II and III were prepared inthe following manner and their stability was studied under theconditions described below:

Form I:

A 250 ml flask equipped with overhead stirrer and gas inlet was chargedwith 34 g of bupropion base and 138 ml of isopropanol. The solution wasmaintained under stirring while 13 g of gaseous HBr was introducedthrough the gas inlet in a time of 20′ while the internal temperature ofthe mixture raises from 25 to 40° C. During the gas addition a heavywhite precipitate formed. At the end of the gas addition the temperatureof the mixture was raised to reflux (80° C.), to get complete solutionof the suspended solid. The temperature was then lowered to 25° C. in 1hour and further lowered to 0-5° C. in 1 additional hour. Theprecipitate obtained was filtered and washed with 20 ml of coldisopropanol. The discharged wet solid was dried under vacuum (30 mmHg)in a static drier at 50° C. for 16 hours. 34 g of bupropion hydrobromideform I were obtained.

Samples of bupropion HBr form I were subjected to the conditions for theaccelerated stability study as described in Example 10 and the shelflife stability study as described in Example 1. PXRD studies carried outafter 3 months and 6 months for each sample gave the same results. ThePXRD profile of one of the samples after 6 months in the acceleratedstability condition is provided in FIG. 60.

Form II:

10 g of bupropion HBr form I were dissolved in a mixture of 170 ml ofacetone and 7 ml of water. The mixture was brought to reflux withdissolution of the solid. The solution was then cooled to roomtemperature. After one night the precipitate formed was filtered anddried at 40° C. under vacuum (30 mmHg) for 12 hours. 2.4 g of bupropionHBr form II were obtained. A sample of the product was prepared for anaccelerated stability test, in ICH (International Conference onHarmonisation of Technical Requirements for Registration ofPharmaceuticals for Human Use) conditions (40° C./75% r.h.), by sealingthe product in polyethylene bags, which in turn were placed in aluminumbags containing silica and sealed and placed in the stability chamber inICH conditions (40° C./75% r.h.). The crystalline form was checked aftermaintaining the product under these conditions for 1 month. The PXRDprofile shown in FIG. 61 shows that the compound is still in form II.This demonstrates the stability of crystal form II under theseconditions.

Form III:

20 g of bupropion hydrobromide form 1 and 96 ml of absolute ethanol wereplaced in a 250 ml flask. The mixture was brought to reflux obtainingcomplete dissolution of the solid. The solution was then cooled to roomtemperature without stirring and left in these conditions for 18 hours.The resulting crystalline solid was then filtered and dried under vacuum(30 mmHg) at 50° C. for 4 hours. 11.2 g of bupropion HBr form III wereobtained. A sample of the product was prepared for stability testing bysealing the product in polyethylene bags, which in turn were placed inaluminum bags containing silica and sealed, and placed in the stabilitychamber in ICH conditions (40° C./75% r.h.). The crystalline form waschecked after maintaining the product in these conditions for 1 month.The PXRD profile shown in FIG. 62 demonstrates that the product is notstable in this form under these conditions, as the majority of theproduct changed to form II.

Example 13 HBr-SR Tablets for 100 and 150 mg Strength as Alternate toHCl-SR

Formulation to be based on options used during the development of theWellbutrin HCl SR 100 and 150 mg.

Bupropion HCl was replaced with HBr and adjusted to obtain same amountBupropion base.

Filler materials adjusted accordingly in order to obtain the same tabletcore weights. e.g. 150 mg HCl=130 mg base=174 mg HBr

100 mg=86.7=116

HBr Granulation Process:

Bupropion HBr is granulated with an aqueous solution containingPolyvinyl Alcohol and Stabilizing agent such as Oxalic acid or Succinicacid or Aspartic acid or other suitable acid compounds, in a Fluid bedgranulator.

The dry granules are than mixed with water soluble polymer or mixturesof hydrophobic/hydrophilic polymers at various viscosity grades. Intrials used Hypromellose (Hydroxypropyl methylcelluloseK4M CR grade) aswell as Hydroxypropyl Cellulose (HPC) at quantities to obtain targetrelease.

Microcrystalline Cellulose (MCC) was used as filler and bindingmaterial. Could be replaced with Lactose. For final lubrication GlycerylBehenate (Compritol 888 ATO) was used. Other suitable lubricant such asStearic Acid, Sodium Fumarate are suitable.

The compressed tablets are then coated with a non-functional coloredfilm coating solution.

Formulation example: mg/unit (Target weight 400 mg) for 174 mg strength(equivalent to 150 mg HCl)

Bupropion HBr 174 mg Polyvinyl Alcohol 16 Stabilizer 20 HPMC (HPC) 40MCC 144 Glyceryl Behenate 6Coating: Opadry provided by Colorcon, approximately 3-4% weight gainAbove formulation(s) are evaluated without use of stabilizers.

Example 14 Further Stability Studies Stability of Bupropion HBr 348 MgTablets

In these studies, the stability of bupropion HBr tablets (Lot#Bup-HBr-XL-348-025-5 (7, 30 and 90 counts) were tested after storage at40 degrees C. and 75% relative humidity as described previously for 348mg tablets prepared as described above and having the tablet compositionshown in Table 99. These experiments evaluated the results ofaccelerated stability of the bupropion HBr XL 348 mg tablets packaged in7, 30 and 90 counts based on a comparison of the changes in physicalappearance, assay, the level of the known degradation impurities and thedissolution profiles of the 1, 2, 3 and 6M time points within theinitial data.

No significant changes were observed in physical appearance, and theassay values of the tablets for all counts, however, as expected, therewere gradual increase in the levels of two major known degradationimpurities (3-CBZ and 852U77) and going from 7 to 90 counts, thepercentages of the latter two impurities were varied. The dissolutionprofiles of the drug product for all counts were lower at the firstmonth for all time points in comparison with the initial profile,however, other stability time points varied, for example:

7 Counts: the 2M and 3M were similar to the initial and 6M similar tothe 1M.

30 Counts: The 6M was similar to the 1M and lower than the initial, the2 & 4 hours time points for 2M and 3M were similar to the initial,however, the 8 & 16 hours time points were lower than the correspondingvalues.

90 Counts: Essentially lower dissolution profiles were observed for 2M,3M, and 6M in comparison with the initial profiles These results arecontained in FIG. 63.

Example 15 Additional Stability Testing of 150 Mg, 300 Mg Bupropion HBrTablets (Lot #Bup-Hbr-Ea-150-002-5 and Bup-Hbr-300-001-5)

The same criteria were used to evaluate the stability of Bupropion HBrEA 150 and 300 mg drug products for the 90 counts. Similar results wereobtained for the two drug products as compared with the bupropion HBr XL348 XL 348 mg tablet-90 counts, however, better dissolution stabilitydata were observed, i.e., no significant differences of the dissolutionprofiles for 1M, 2M, 3M, & 6M were observed for the two EA products incomparison with their corresponding initials, except the 6M dissolutiondata for the 300 mg which showed slightly lower values. These resultsare in FIG. 64.

Example 16 Additional Open Dish-Closed Bottle Stability Studies

Experiments were conducted comparing the stability of bupropion HBr XL174 mg core, Bupropion HBr XL 348 core, Bupropion HCl XL 150 mg Core andBupropion HCl XL 300 mg core over 10 and 20 days under open bottle andclosed bottle conditions. These studies were again effected at 40degrees C. and 75% relative humidity. Degradation was again assessed byassaying for known impurities 3-CBZ and 852U77. As before the bupropionHBr cores were less subject to degradation than the bupropion HCl coresunder open and closed bottle conditions. These results are contained inFIG. 65.

Example 17 Dissolution of Bupropion Formulations According to theInvention in Different USP-3 Media

The dissolution of bupropion HBr formulations according to the inventionwere assessed in three USP-3 media, i.e., SGF pH 1.2, Acetate Buffer pH4.5 and Phosphate Buffer pH 6.8 over a period of 16 hours. These resultsare contained in FIG. 66. Particularly Bupropion HBr XL 348 mg tablets(final), Lot #Bup-HBr-XL-012-5; Wellbutrin XL 300 mg tablets (final),Lot #05A116; Bupropion HBr XL 348 mg tablets ECl Lot #Bup-HBr-XL-012-5(EC 32 mg wg) and Wellbutrin XL 300 mg tablets (ECl0-Lot #05D047 wereassessed in SGF media pH 1.2 for 2 hours, Acetate Buffer pH 4.5 for 2hours, and Phosphate Buffer SIF pH 6.8 for a total of 10 hours. Theresults are contained in the FIG. 66-68.

Additionally, FIG. 66 contains the results of dissolution testing of abupropion HBr formulation according to the invention, i.e., bupropionHBr 348 mg, lot #05E304, versus BupHCl 300 mg (Bup 300XL Target) lot#01L238 in vivo and BUP 300XL Target in USP3-0.5% SLS media over timesranging from 0 to 16 hours.

Additionally the same Figure tabulates the results of these dissolutionexperiments comparing % drug release over time for bupropion HBr 348 mgLot #05E304 in USP-3 media (SGF pH 1.2 and 0.5% SLS after 2 hours,Acetate Buffer pH 4.5 after 2 hours and Phosphate Buffer pH 6.8 after atotal of 16 hrs.

Also, FIG. 68 contains comparative dissolution profiles for BupropionHBr XL 348 mg final, Wellbutrin XL EC, tablets in different USP-3 media(SGF pH 1.2, acetate buffer pH 4.5 and phospate buffer pH 6.8) comparedagainst in vivo data for Bupropion HCl 150 mg XL target (Lot 02A063)over a period of 16 hours.

TABLE 1 Assay of bupropion salts by HPLC Tartrate Tartrate Test MaleateTosylate Fumarate HBr Succinate acid neutral Citrate Assay 99.7% 97.4%89.8% 99.7% 97.6 84.9% 51.7%* 85.0%

TABLE 2 moisture content and pH of aqueous solutions: Afterrecrystallization (R&D) Original Tested after (Initial APIs) 1 dayTested after pH pH 2 Months Sample ID KF (aq. 0.5%) KF (aq. 0.5%) KFBup-HCl 0.0 5.90 Bup-Maleate 0.10 4.29 Bup-Tosylate 1.71* 5.56 023 5.880.18 Bup-Fumarate 0.09 3.84 Bup-HBr 0.00 5.92 Bup-Succinate 0.13 4.82Bup-Tartrate 0.18 3.62 Bup-Tartrate 0.14 3.62 neutral Bup-Citrate (I)0.23 3.89 *KF after 3M = 1.80% Bup = bupropion

TABLE 3 Solubility & other physical properties: Bupropion HBr vsBupropion HCl. Solubility (mg/ml) Sample ID Water EtOH IPA Bupropion HCl270 80 10 Bupropion HBr 143 92 12 Moisture PS Content pH MP Sample ID(Malvern) (KF) (aq. 0.5%) (DSC) Bupropion HCl  10% 32 μm 0.01% 5.90243.6 C. (Erregierre) 50% 102 μm 90% 276 μm Bupropion HBr  10% 72 μm0.00% 5.92 234.1 C. (Chemi) 50% 245 μm 90% 657 μm

TABLE 4 40° C./75% RH Close Vial (DS + (DS + (DS + (DS + Placebo)¹ +Placebo)¹ Placebo)¹ + Placebo)¹ + (Water + (IPA + EtOH)⁴ Water² EtOH +IPA)³ ¹300 mg of the drug substance was placed in a 2 mL vial, then 100mg placebo (almost double of the required amount) was added, and mixedwell. ²Two drops of water was added to the spiked placebo and mixed wellwith a spatula, then closed with a cup. ³A mixture of equal volume ofwater, EtOH and IPA was prepared. Two drops of the latter mixture wasadded to the spiked placebo, and mixed well with a spatula, then closedwith a cup. ⁴A mixture of equal volume of EtOH and IPA was prepared. Twodrops of the latter mixture was added to the spiked placebo, and mixedwell with a spatula, then closed with a cup.

TABLE 5 # of Stability Quantity/ glass bottle pulling time API ID Lot#bottle 40° C./75% RH (Day) Bupropion HBr STN07492 348 mg 2 14 & 24Bupropion HCl STN06973 300 mg 2 14 & 24 Bupropion HBr STN07491 348 mg 110 STN07492 348 mg 1 10 Bupropion HCl STN06973 300 mg 1 10 STN06978 300mg 1 10

TABLE 6 Closed glass bottle stability studies (40° C./75% RH) onBupropion-HBr & HCl APIs. Bupropion HBr, Bupropion HCl, Lot# STN07492 L#STN06973 Tests Initial 14-Days 24 Days Initial 14-Days 24 Days % Assay99.6 98.8 99.5 100.4 98.5 98.5 % Impurities 0.007 0.015 0.022 0.0020.019 0.082 3-CBZ 852U77 0.009 0.058 0.052 0.003 0.010 0.023 20U78/dilu0.044 0.048 0.038 0.043 0.038 0.040 827U76 ND 0.012 0.016 ND ND 0.102Total 0.098 0.105 0.104 0.044 0.038 0.049 unknown Total (%) 0.16 0.230.23 0.09 0.11 0.30

TABLE 7 Closed glass bottle stability studies (40 C./75% RH) onBupropion HCl & Bupropion HBr APIs. Bupropion HBr, Bupropion HBr, Lot#STN07491 Lot# STN07492 Tests Initial 10-Days Initial 10 Days % Assay99.5 98.2 99.6 99.2 % Impurities 0.011 0.070 0.007 0.031 3-CBZ 852U77 ND0.125 ND 0.055 20U78/dilu 0.041 0.051 0.041 0.044 827U76 ND 0.039 ND NDTotal unknown 0.129 0.129 0.194 0.15 Total (%) 0.17 0.42 0.23 0.24Bupropion HCl, Bupropion HCl, Lot# STN06973 Lot# STN06978 Tests Initial10-Days Initial 10 Days % Assay 99.4 96.3 99.1 96.5 % Impurities 0.0030.110 0.002 0.278 3-CBZ 852U77 ND 0.047 ND 0.124 20U78/dilu 0.040 0.0470.04 0.057 827U76 ND 0.045 ND 0.141 Total unknown 0.053 0.187 0.1650.137 Total (%) 0.10 0.44 0.21 0.74

TABLE 8 Each trial's contents and amounts of each material per partAmount (g) Materials Part 1 Part 2 Part 3 Part 4 Part 5 Bupropion HBr2062.5 2062.5 2062.5 2062.5 2062.5 PVA 68.75 68.75 68.75 68.75 68.75Purified Water 1452.5 1452.5 1452.5 1452.5 1452.5

TABLE 9 Summary of specifications for granulation procedure.Specification Range Target Fan Speed Slow Slow Air Volume (CMH) 60-65 65Exhaust Temperature (° C.) 35-45 40 Supply Temperature (° C.) 60-65 65Product Temperature (° C.) 35-55 45 Atomizing Air Pressure (Bar/psi) 3535 Pump Speed (rpm) 18 18 Liquid Flow Rate (g/min) 13 13 Bed Dew Point(MMWC) 0 0 Filter Dew Point (MMWC 100-300 200

TABLE 10 The amount of lubricant in the final formulation was 343.75 g,which was 3.125% of the total. Materials Amount (g) Part 1 2131.25 Part2 2131.25 Part 3 2131.25 Part 4 2131.25 Part 5 2131.25 Compritol 888343.75 Total 11000.0

TABLE 11 Summary of Specifications for Tablet Press Set-up. ParametersSettings/Ranges Pre-Compression Thickness (mm) 2 Control Thickness (mm)1.5 Fill Thickness (mm) 7-8 Overload Pressure (Tons) 1.5-2.0 Tablets perminute 450-500 Feeder Speed 1-2 Feeder Control Auto

TABLE 12 Summary of specifications for compression Specification forSpecification for Parameters 174 mg Tablet 348 mg Tablet IndividualTablet Weight 185.6 ± 5% 371.2 ± 5% (mg) (176.3 mg-194.9 mg) (352.6mg-389.8 mg) Average Tablet Weight 185.6 ± 3% 371.2 ± 3% (mg) (180.0mg-191.2 mg) (360.1 mg-382.3 mg) Tablet Hardness (SC)  6.0-12.0 6.0-12.0 Tablet Thickness (mm) 5.0-6.0 4.5-5.0 Friability (%) <0.8 <0.8

TABLE 13 Formulations used as the Ethocel coating on the 174 mg and 348mg Bupropion HBr cores. FORMULATION 1 FORMULATION 2 FORMULATION 3Ethocel (Ethyl Ethocel (Ethyl Ethocel (Ethyl Cellulose) Cellulose)Cellulose) Standard 100 Standard 100 Standard 100 Premium PremiumPremium Povidone USP Povidone USP Povidone USP (Kollidone 90F)(Kollidone 90F) (Kollidone 90F) Polyethylene Polyethylene PolyethyleneGlycol 4000 Glycol 4000 Glycol 4000 Ethyl Alcohol Dibutyl Sebacate EthylAlcohol 95% USP Ethyl Alcohol 95% USP 95% USP Isopropyl Alcohol (IPA)

TABLE 14 Formulations used as the Final Coats on the 174 mg and 348 mgBupropion HBr tablets. FORMULATION A FORMULATION B Eudragit L30D-55Eudragit L30D-55 Chroma-Tone DEB 5156-CLE Syloid 244FP Purified WaterPolyethylene Glycol 4000 Triethyl Citrate Purified Water

TABLE 15 Summary of Specifications that were kept constant in theEthocel coating Process. Process Parameters Operational Ranges TargetInlet Temperature for coating (° C.) SV: 40 ± 5 40 PV: 40 ± 5 InletTemperature for Drying (° C.) 30-35 35 Exhaust Temperature 30 ± 10 30Product Temperature 25-35 28 ΔP Differential Pressure (W · C)(−0.1)-(0.12) −0.10 Supply Air Flow (CFM) 200 ± 50  200 Pan Speed (rpm)2.5-12  5.0 Atomizing Air (psi) 35-40 35 Pattern Air (psi) 20-30 25Spray Rate (g/min)  5-15 6.0

TABLE 16 Summary of Specifications that were kept constant in the Finalcoating Process. Process Parameters Operational Ranges Target InletTemperature for coating (° C.) SV: 50 ± 5 50 PV: 50 ± 5 InletTemperature for Drying (° C.) 40 ± 5 40 Exhaust Temperature 35 ± 5 38Product Temperature 35 ± 2 35 ΔP Differential Pressure (W · C)(−0.1)-(0.12) −0.10 Supply Air Flow (CFM) 200 ± 50 200 Pan Speed (rpm)2.5-15  12.0 Atomizing Air (psi) 25-35 35 Pattern Air (psi) 20-30 25Spray Rate (g/min)  5-15 13.0

TABLE 17 Materials used in one part of the batch, the percentage of eachconstituent, the amount per tablet and the amount per batch, forBUP-HBr-XL-009-5 Materials % mg/tablet Batch Quantity (g) Bupropion HBr93.75 348.00 1993.75 PVA 3.125 11.60 68.75 Compritol 888 3.125 11.6068.75 Total 100.00 371.2 mg 2131.25

TABLE 18 Results obtained using 9 mm tooling for batch BUP-HBr-XL-009-5.Parameters Theoretical Actual Average Individual Tablet Weight 371.2 mg371.5 mg Average Hardness 6.0-12.0 SC 10.77 SC Average Thickness 5.0-6.0mm 5.60 mm Friability <0.8% 0%

TABLE 19 Results obtained using 10 mm tooling for batchBUP-HBr-XL-009-5. Parameters Theoretical Actual Average IndividualTablet Weight 371.2 mg 366.5 mg Average Hardness 6.0-12.0 SC 7.50 SCAverage Thickness 5.0-6.0 mm 4.97 mm Friability <0.8% 0%

TABLE 20 Materials used in one part of the batch, the percentage of eachconstituent, the amount per tablet and the amount per batch for batchBUP-HBr-XL-021-5. Materials % mg/tablet Batch Quantity (g) Bupropion HBr93.75 174.00 1993.75 PVA 3.125 5.80 68.75 Compritol 888 3.125 5.80 68.75Total 100.00 185.60 2131.25

TABLE 21 Results obtained using 7 mm tooling for batch BUP-HBr-XL-021-5.Parameters Theoretical Actual Average Individual Tablet Weight 185.6 mg186.8 mg Average Hardness 6.0-12.0 SC 9.23 SC Average Thickness 4.5-5.0mm 4.70 mm Friability <0.8% 0%

TABLE 22 Materials used in the EC coating and their quantities for batchBUP-HBr-XL-348-013-5. % Con- tribution Batch to Total Quantity % ofSolids Materials Solution (g) in Solution Ethocel (Ethyl Cellulose) 3.6077.44* 38.74 Standard 100 Premium Povidone USP (Kollidone 90F) 4.60099.22* 49.64 PEG 4000 1.07 23.23* 11.62 Ethyl Alcohol 95% USP 86.441859.50 N/A Isopropyl Alcohol 99% USP 4.54 97.87 N/A Total 100.002151.00 100.00 *Total solid component of the formulation included 77.44g of Ethocel, 99.22 g of Povidone and 23.23 g of PEG 4000, which gave atotal solid amount of 199.89 g. The solid component of the formulationmade up 9% of the total solution and the remaining 91% was made up ofliquid.

TABLE 23 Theoretical and Actual Tablet weights at 28 mg, 30 mg, 32 mgand 34 mg weight gains for batch BUP-HBr-XL-348-013-5. Weight Gain (mg)Theoretical Weight (mg) Actual Weight (mg) 28.0 400.0 401.3 30.0 402.0402.6 32.0 404.0 404.5 34.0 406.0 406.8

TABLE 24 Materials used in the Final coating and their quantities forbatch BUP-HBr-XL-348-013-5. % Con- tribution Batch Amount to TotalQuantity of Solid % of Solids Materials Solution (g) (g) in SolutionEudragit L30 D-55 22.73 104.8 31.44 65.00* Chroma-Tone DEB 3.66 16.9016.90 35.00** 5156-CLE Purified Water (1) 21.78 100.40 N/A N/A PurifiedWater (2) 51.89 239.20 N/A N/A Total 100.00 460.95 48.34*** 100.00 *Thepercentage of Eudragit, solid, that contributed to the total amount ofsolid was 65%. **The percentage of Chroma-Tone, solid, that contributedto the total amount of solid was 35%. ***The Total amount of solid(48.34 g) was 10.5% of the total solution.

TABLE 25 Theoretical and Actual Tablet weights at 4 mg, 5 mg, 6 mg and 7mg weight gains. Weight Gain (mg) Theoretical Weight (mg) Actual Weight(mg) 4.0 410.0 410.5 5.0 411.0 410.8 6.0 412.0 412.4 7.0 413.0 413.9

TABLE 26 Materials used in the EC coating and their quantities for batchBUP-HBr-XL-348mg-018-5. % Con- tribution Batch to Total Quantity % ofSolids Materials Solution (g) in Solution* Ethocel (Ethyl Cellulose)3.42 73.57 38.00 Standard 100 Premium Povidone USP (Kollidone 90F) 4.4194.86 49.00 PEG 4000 1.17 25.17 13.00 Ethyl Alcohol 95% USP 86.451859.53 N/A Isopropyl Alcohol 99% USP 4.55 97.87 N/A Total 100.002151.00 100.00 *Total solid included 73.57 g of Ethocel, 94.86 g ofPovidone and 25.17 g of PEG 4000. This gave a total of 193.6 g totalsolid amount.

TABLE 27 Theoretical and Actual Tablet weights at 26 mg, 28 mg, 30 mg,and 32 mg weight gains for batch BUP-HBr-XL-348mg-018-5. Weight Gain(mg) Theoretical Weight (mg) Actual Weight (mg) 26.0 398.0 397.7 28.0400.0 399.5 30.0 402.0 401.5 32.0 404.0 404.0

TABLE 28 Materials used in the Final coating and their quantities forbatch BUP-HBr-XL-348mg-018-5. % Con- tribution Batch Amount to TotalQuantity of Solid % of Solids Materials Solution (g) (g) in SolutionEudragit L30D D-55 22.75 104.86 31.46 65.00* Syloid 244FP 2.62 12.0812.08 25.00** Carbowax 4000 0.70 3.22 3.22 6.65** Triethyl Citrate 0.361.64 1.64 3.39** Purified Water (1) 33.84 156.00 N/A N/A Purified Water(2) 39.73 183.15 N/A N/A Total 100.00 460.95 48.40*** 100.00 *Thepercentage of Eudragit, solid, that contributed to the total amount ofsolid was 65%. **The percentage of Syloid, Carbowax 4000 and TriethylCitrate that contributed to the total amount of solid was 25%, 6.65% and3.39%, respectively. This gave a total of 35%. ***The total amount ofsolid (48.4 g) was 10.5% of the total solution.

TABLE 29 Theoretical and Actual Tablet weights at 4 mg, 5 mg, 6 mg, and7 mg weight gains for batch BUP-HBr-XL-348mg-018-5. Weight Gain (mg)Theoretical Weight (mg) Actual Weight (mg) 4.0 408.0 408.5 5.0 409.0409.3 6.0 410.0 410.7 7.0 411.0 411.1

TABLE 30 Materials used in the EC coating and their quantities for batchBUP-HBr-XL-174mg-022-5. % Con- tribution Batch to Total Quantity % ofSolids Materials Solution (g) in Solution* Ethocel (Ethyl Cellulose)3.60 116.12 40.00 Standard 100 Premium Povidone USP (Kollidone 90F) 4.32139.34 48.00 PEG 4000 1.08 34.84 12.00 Ethyl Alcohol 95% USP 86.452788.54 N/A Isopropyl Alcohol 99% USP 4.55 146.76 N/A Total 100.003225.60 100.00 *Total Solid included 116.12 g of Ethocel, 139.34 g ofPovidone and 34.84 g of PEG 4000. This gave a total solid amount of290.3 g.

TABLE 31 Theoretical and Actual Tablet weights at 20 mg, 22 mg, 24 mg,26 mg, 28 mg, 29 mg, and 30 mg weight gains for batchBUP-HBr-XL-174mg-022-5. Weight Gain (mg) Theoretical Weight (mg) ActualWeight (mg) 20.0 206.0 206.1 22.0 208.0 207.8 24.0 210.0 210.2 26.0212.0 211.5 28.0 214.0 213.7 29.0 215.0 214.9 30.0 216.0 216.5

TABLE 32 Materials used in the Final coating and their quantities forbatch BUP-HBr-XL-174mg-022-5. % Con- tribution Batch Amount to TotalQuantity of Solid % of Solids Materials Solution (g) (g) in SolutionEudragit L30D D-55 22.75 104.86 31.46 65.0* Syloid 244FP 2.62 12.0812.08 25.0** Carbowax 4000 0.70 3.22 3.22 6.65** Triethyl Citrate 0.361.64 1.64 3.39** Purified Water (1) 33.84 156.00 N/A N/A Purified Water(2) 39.73 183.15 N/A N/A Total 100.00 460.95 48.40*** 100.00 *Thepercentage of Eudragit, solid, that contributed to the total amount ofsolid was 65%. **The percentage of Syloid, Carbowax 4000 and TriethylCitrate that contributed to the total amount of solid was 25%, 6.65% and3.39%, respectively. This gave a total of 35%. ***The Total amount ofsolid (48.4 g) was 10.5% of the total solution.

TABLE 33 Theoretical and Actual Tablet weights at 4 mg, 5 mg, 6 mg, and7 mg weight gains for batch BUP-HBr-XL-174mg-022-5. Weight Gain (mg)Theoretical Weight (mg) Actual Weight (mg) 4.0 219.0 219.4 5.0 220.0220.2 6.0 221.0 221.2 7.0 222.0 223.0

TABLE 34 Materials used in the EC coating and their quantities for batchBUP-HBr-XL-348mg-023-5. % Con- tribution Batch to Total Quantity % ofSolids Materials Solution (g) in Solution* Ethocel (Ethyl Cellulose)3.69 79.37 42.71 Standard 100 Premium Povidone USP (Kollidone 90F) 3.6979.37 42.71 PEG 4000 1.26 27.11 14.58 Dibutyl Sebacate, NF 0.36 7.75 N/AEthyl Alcohol 95% USP 91.00 1957.4 N/A Total 100.00 2151.00 100.00*Total Solid includes 79.37 g of Ethocel, 79.37 g of Povidone, 27.11 gof PEG 4000 and 7.75 g of Dibutyl Sebacate. This gave a total solidamount of 193.6 g.

TABLE 35 Theoretical and Actual Tablet weights at 26 mg, 28 mg, 30 mg,and 32 mg weight gains for batch BUP-HBr-XL-348mg-023-5. Weight Gain(mg) Theoretical Weight (mg) Actual Weight (mg) 26.0 398.0 399.3 28.0400.0 401.0 30.0 402.0 401.7 32.0 404.0 402.7

TABLE 36 Materials used in the EC coating and their quantities for batchBUP-HBr-XL-348mg-025-5. % Con- tribution Batch to Total Quantity % ofSolids Materials Solution (g) in Solution* Ethocel (Ethyl Cellulose)3.69 79.40 41.00 Standard 100 Premium Povidone USP (Kollidone 90F) 3.7881.30 42.00 PEG 4000 1.53 32.90 17.00 Ethyl Alcohol 95% USP 91.001957.40 N/A Total 100.00 2151.00 100.00 *Total Solid included 79.40 g ofEthocel, 81.30 g of Povidone and 32.90 g of PEG 4000. This gave a totalsolid amount of 193.6 g.

TABLE 37 Theoretical and Actual Tablet weights at 26 mg, 28 mg, 30 mg,and 32 mg weight gains for batch BUP-HBr-XL-348mg-025-5. Weight Gain(mg) Theoretical Weight (mg) Actual Weight (mg) 26.0 398.0 397.8 28.0400.0 400.6 30.0 402.0 401.4 32.0 404.0 402.2

TABLE 38 Materials used in the Final coating and their quantities forbatch BUP-HBr-XL-348mg-025-5. % Con- tribution Batch Amount to TotalQuantity of Solid % of Solids Materials Solution (g) (g) in SolutionEudragit L30D D-55 19.77 91.13 27.34 56.50* Syloid 244FP 3.15 14.5214.52 30.00** Carbowax 4000 0.95 4.36 4.36 9.00** Triethyl Citrate 0.472.17 2.17 4.50** Purified Water (1) 21.70 100.00 N/A N/A Purified Water(2) 53.96 248.77 N/A N/A Total 100.00 460.95 48.39*** 100.00 *Thepercentage of Eudragit, solid, that contributed to the total amount ofsolid was 65%. **The percentage of Syloid, Carbowax 4000 and TriethylCitrate that contributed to the total amount of solid was 30%, 9% and4.5%, respectively. This gave a total of 43.5%. ***The Total amount ofsolid (48.39 g) was 10.5% of the total solution.

TABLE 39 Theoretical and Actual Tablet weights at 4 mg, 5 mg, 6 mg, and7 mg weight gains for batch BUP-HBr-XL-348mg-025-5. Weight Gain (mg)Theoretical Weight (mg) Actual Weight (mg) 4.0 408.0 408.3 5.0 409.0408.8 6.0 410.0 409.5 7.0 411.0 411.1

TABLE 40 Materials used in the EC coating and their quantities for batchBUP-HBr-XL-348mg-026-5. % Con- tribution Batch to Total Quantity % ofSolids Materials Solution (g) Solution* Ethocel (Ethyl Cellulose) 3.6979.37 41.00 Standard 100 Premium Povidone USP (Kollidone 90F) 3.69 79.3741.00 PEG 4000 0.36 7.75 4.00 Dibutyl Sebacate, NF 1.26 27.11 14.00Ethyl Alcohol 95% USP 91.00 1957.4 N/A Total 100.00 2151.00 100.00*Total Solid included 79.37 g of Ethocel, 79.37 g of Povidone, 7.75 g ofPEG 4000 and 27.11 g of Dibutyl Sebacate. This gave a total solid amountof 193.6 g.

TABLE 41 Theoretical and Actual Tablet weights at 26 mg, 28 mg, 30 mg,and 32 mg weight gains for batch BUP-HBr-XL-348mg-026-5. Weight Gain(mg) Theoretical Weight (mg) Actual Weight (mg) 26.0 398.0 398.8 28.0400.0 400.5 30.0 402.0 402.5 32.0 404.0 403.6

TABLE 42 Materials used in the EC coating and their quantities for batchBUP-HBr-XL-174mg-027-5. % Con- tribution Batch to Total Quantity % ofSolid Materials Solution (g) in Solution* Ethocel (Ethyl Cellulose) 3.69138.87 41.00 Standard 100 Premium Povidone USP (Kollidone 90F) 3.78142.25 42.00 PEG 4000 1.53 57.58 17.00 Ethyl Alcohol 95% USP 91.003424.63 N/A Total 100.00 3763.33 100.00 *Total Solid included 138.87 gof Ethocel, 142.25 g of Povidone and 57.58 g of PEG 4000. This gave atotal solid amount of 338.7 g.

TABLE 43 Theoretical and Actual Tablet weights at 22 mg, 24 mg, and 26mg weight gains for batch BUP-HBr-XL-174mg-027-5. Weight Gain (mg)Theoretical Weight (mg) Actual Weight (mg) 22.0 208.0 207.7 24.0 210.0210.8 26.0 212.0 212.4

TABLE 44 Materials used in the Final coating and their quantities forbatch BUP-HBr-XL-174mg-027-5. % Con- tribution Batch Amount to TotalQuantity of Solid % of Solids Materials Solution (g) (g) in SolutionEudragit L30D D-55 19.77 182.27 54.68 56.5* Syloid 244FP 3.15 29.0329.03 30.0** Carbowax 4000 0.95 8.71 8.71 9.0** Triethyl Citrate 0.474.35 4.35 4.5** Purified Water (1) 21.70 200.00 N/A N/A Purified Water(2) 53.98 497.26 N/A N/A Total 100.00 921.62 96.77*** 100.00 *Thepercentage of Eudragit, solid, that contributed to the total amount ofsolid was 56.5%. **The percentage of Syloid, Carbowax 4000 and TriethylCitrate that contributed to the total amount of solid was 30.0%, 9.0%and 4.5%, respectively. This gave a total of 43.5%. ***The Total amountof solid (9.77 g) was 10.5% of the total solution.

TABLE 45 Theoretical and Actual Tablet weights at 4 mg, 5 mg, 6 mg, and7 mg weight gains for batch BUP-HBr-XL-174mg-027-5. Weight Gain (mg)Theoretical Weight (mg) Actual Weight (mg) 4.0 216.0 216.6 5.0 217.0217.6 6.0 218.0 217.8 7.0 219.0 219.8

TABLE 46 Each trial's contents and amounts of each material per part forEA formulation. Amount (g) Materials Part 1 Part 2 Part 3 Part 4 Part 5Bupropion HBr 2062.5 2062.5 2062.5 2062.5 2062.5 PVA 68.75 68.75 68.7568.75 68.75 Purified Water 1452.5 1452.5 1452.5 1452.5 1452.5

TABLE 47 Summary of specifications for granulation procedure for EAformulations. Specification Setting/Range Target Fan Speed Slow Slow AirVolume (CMH) 60-65 65 Exhaust Temperature (° C.) 35-45 40 SupplyTemperature (° C.) 60-65 65 Product Temperature (° C.) 35-55 45Atomizing Air Pressure (Bar/psi) 35 35 Pump Speed (rpm) 18 18 LiquidFlow Rate (g/min) 13 13 Bed Dew Point (MMWC)  0 0 Filter Dew Point (MMWC100-300 200

TABLE 48 The amount of lubricant in the final EA formulation was 343.75g, which was 3.125% of the total. Materials Amount (g) Bupropion HBrGranules 10656.25 Compritol 888 343.75 Total 11000

TABLE 49 Summary of Specifications for Tablet Press Set-up for the EAformulation. Parameters Settings/Ranges Pre-Compression Thickness (mm) 2Control Thickness (mm) 1.5 Fill Thickness (mm) 7-8 Overload Pressure(Tons) 1.5-2.0 Tablets per minute 450-500 Feeder Speed 1-2 FeederControl Auto

TABLE 50 Summary of specifications for compression for the EAformulation. Specification for Specification for Parameters 150 mgTablet 300 mg Tablet Individual Tablet Weight 160.0 ± 5% 320.0 ± 5% (mg)(152.0 mg-168.0 mg) (304.0 mg-336.0 mg) Average Tablet Weight 160.0 ± 3%320.0 ± 3% (mg) (155.2 mg-164.8 mg) (310.4 mg-329.6 mg) Tablet Hardness(SC)  6.0-12.0  6.0-12.0 Tablet Thickness (mm) 5.0-6.0 4.5-5.0Friability (%) <0.8 <0.8

TABLE 51 Formulations used as the Ethocel coating on the 150 mg and 300mg Bupropion HBr EA cores. FORMULATION 1 FORMULATION 2 FORMULATION 3FORMULATION 4 Ethocel Ethocel Ethocel Ethocel (Ethyl Cellulose) (EthylCellulose) (Ethyl Cellulose) (Ethyl Cellulose) Standard 100 Standard 100Standard 100 Standard 100 Premium Premium Premium Premium Povidone USPPovidone USP Povidone USP Povidone USP (Kollidone 90F) (Kollidone 90F)(Kollidone 90F) (Kollidone 90F) Polyethylene Glycol Polyethylene GlycolDibutyl Sebacate Polyethylene Glycol 4000 4000 Ethyl Alcohol 4000 EthylAlcohol Dibutyl Sebacate 200 proof Ethyl Alcohol 200 proof Ethyl Alcohol95% USP 200 proof

TABLE 52 Summary of Specifications that were kept constant in theCoating Process for the EA formulations. Process Parameters RangesTarget Inlet Temperature for coating SV: 50 ± 5 50 (° C.) PV: 50 ± 5Inlet Temperature for Drying 40 ± 5 40 (° C.) Exhaust Temperature 35 ± 535 Product Temperature 35 ± 2 35 ΔP Differential Pressure (W.C)(−0.1)-(0.12) −0.10 Supply Air Flow (CFM) 200 ± 50 200 Pan Speed (rpm)2.5-15  12.0 Atomizing Air (psi) 25-35 35 Pattern Air (psi) 20-30 25Spray Rate (g/min)  5-15 13

TABLE 53 Materials used in the batch, the percentage of eachconstituent, the amount per 300 mg EA tablet and the amount per batch.Materials % mg/tablet Batch Quantity (g) Bupropion HBr 93.75 300.001993.75 PVA 3.125 10.00 68.75 Compritol 888 3.125 10.00 68.75 Total100.00 320.0 mg 2131.25

TABLE 54 Materials used in the batch, the percentage of eachconstituent, the amount per 150 mg EA tablet and the amount per batch.Materials % mg/tablet Batch Quantity (g) Bupropion HBr 93.75 150.001993.75 PVA 3.125 5.00 68.75 Compritol 888 3.125 5.00 68.75 Total 100.00160.0 mg 2131.25

TABLE 55 Results obtained using 9 mm tooling (EA formulations).Parameters Theoretical Actual Average Individual Tablet Weight 372.0 mg371.5 mg Average Hardness 6.0-12.0 SC 10.77 SC Average Thickness 5.0-6.0mm 5.60 mm Friability <0.8% 0%

TABLE 56 Results obtained using 7 mm tooling (EA formulations).Parameters Theoretical Actual Average Individual Tablet Weight 372.0 mg366.5 mg Average Hardness 6.0-12.0 SC 7.50 SC Average Thickness 5.0-6.0mm 4.97 mm Friability <0.8% 0%

TABLE 57 Materials used in the EC coating and their quantities for batchBUP-HBr-EA-300mg-001-5. % Con- tribution Batch to Total Quantity % ofSolids Materials Solution (g) in Solution Ethocel (Ethyl Cellulose) 4.94185.62* 55.00 Standard 100 Premium Povidone USP (Kollidone 90F) 2.5294.50* 28.00 PEG 4000 0.77 28.69* 8.50 Dibutyl Sebacate 0.77 28.69* 8.50Ethyl Alcohol Anhydrous 91.0 3412.5 N/A (200 Proof) Total 100.00 3750.00100.00 *Total solid component of the formulation included all thematerial except for the Ethyl Alcohol. This formulation consisted of atotal solid amount of 337.5 g, which made up 9% of the total solution.The remaining 91% was made up of the Ethyl Alcohol 200 proof (liquid).

TABLE 58 Theoretical and Actual EA Tablet weights at 44 mg, 46 mg, 48mg, 50 mg, 52 mg and 54 mg weight gains for batchBUP-HBr-EA-300mg-001-5. Weight Gain (mg) Theoretical Weight (mg) ActualWeight (mg) 44.0 364.0 362.9 46.0 366.0 365.6 48.0 368.0 366.6 50.0370.0 369.3 52.0 372.0 371.7 54.0 374.0 374.8

TABLE 59 Materials used in the EC coating and their quantities for batchBUP-HBr-EA-150mg-002-5. % Con- tribution Batch to Total Quantity % ofSolids Materials Solution (g) in Solution Ethocel (Ethyl Cellulose) 4.94232.03* 55.0 Standard 100 Premium Povidone USP (Kollidone 90F) 2.52118.12* 28.0 PEG 4000 0.77 35.86* 8.5 Dibutyl Sebacate 0.77 35.86* 8.5Ethyl Alcohol Anhydrous 91.0 4265.63 N/A (200 Proof) Total 100.004687.50 100.00 *Total solid included 232.03 g of Ethocel, 118.12 g ofPovidone, 35.86 g of PEG 4000 and 35.86 g of Dibutyl Sebacate. This gavea total solid amount of 421.87 g.

TABLE 60 Theoretical and Actual Tablet weights at 18 mg, 20 mg, 22 mg,24 mg, 26 mg, 28 mg, 30 mg, 32 mg, 34 mg, and 36 mg weight gains forbatch BUP-HBr-EA-150mg-002-5. Weight Gain (mg) Theoretical Weight (mg)Actual Weight (mg) 18.0 178.0 178.2 20.0 180.0 181.0 22.0 182.0 181.824.0 184.0 184.3 26.0 186.0 185.8 28.0 188.0 188.1 30.0 190.0 190.7 32.0192.0 192.5 34.0 194.0 193.7 36.0 196.0 195.5

TABLE 61 Materials used in the EC coating and their quantities for batchBUP-HBr-EA-300mg-003-5. % Con- tribution Batch to Total Quantity % ofSolids Materials Solution (g) in Solution Ethocel (Ethyl Cellulose) 4.94185.62* 55.00 Standard 100 Premium Povidone USP (Kollidone 90F) 2.5294.50* 28.00 Dibutyl Sebacate 1.54 57.38* 17.00 Ethyl Alcohol Anhydrous91.0 3412.5 N/A (200 Proof) Total 100.00 3750.0 100.00 *Total Solidincluded 185.62 g of Ethocel, 94.50 g of Povidone and 57.38 g of DibutylSebacate. This gave a total solid amount of 337.5 g.

TABLE 62 Theoretical and Actual Tablet weights at 44 mg, 46 mg, 48 mg,50 mg, 52 mg, and 54 mg weight gains for batch BUP-HBr-EA-300mg-003-5.Weight Gain (mg) Theoretical Weight (mg) Actual Weight (mg) 44.0 364.0364.7 46.0 366.0 365.8 48.0 368.0 367.7 50.0 370.0 369.7 52.0 372.0371.9 54.0 374.0 372.9

TABLE 63 Materials used in the EC coating and their quantities for batchBUP-HBr-EA-300mg-004-5. % Con- tribution Batch to Total Quantity % ofSolids Materials Solution (g) in Solution Ethocel (Ethyl Cellulose) 4.94185.62* 55.00 Standard 100 Premium Povidone USP (Kollidone 90F) 2.5294.50* 28.00 PEG 4000 1.54 57.38* 17.00 Ethyl Alcohol Anhydrous 91.003412.50 N/A (200 Proof) 0 0 0 Total 100.00 3750.00 100.00 *Total Solidamount included 185.62 g of Ethocel, 94.50 g of Povidone and 57.38 g ofPEG 4000. This gave a total solid amount of 337.5 g.

TABLE 64 Theoretical and Actual Tablet weights at 44 mg, 46 mg, 48 mg,50 mg, 52 mg, and 54 mg weight gains for batch BUP-HBr-EA-300mg-004-5.Weight Gain (mg) Theoretical Weight (mg) Actual Weight (mg) 44.0 364.0363.6 46.0 366.0 365.5 48.0 368.0 368.5 50.0 370.0 370.2 52.0 372.0372.6 54.0 374.0 374.3

TABLE 65 Materials used in the EC coating and their quantities for batchBUP-HBr-EA-300mg-005-5. % Con- tribution Batch to Total Quantity % ofSolids Materials Solution (g) in Solution Ethocel (Ethyl Cellulose) 4.94185.62* 55.00 Standard 100 Premium Povidone USP (Kollidone 90F) 2.5294.50* 28.00 PEG 4000 0.77 28.69* 8.50 Dibutyl Sebacate 0.77 28.69* 8.50Ethyl Alcohol Anhydrous 91.00 3412.50 N/A (200 Proof) Total 100.003750.0 100.00 *Total Solids included 185.62 g of Ethocel, 94.50 g ofPovidone, 28.69 g of PEG 4000 and 28.69 g of Dibutyl Sebacate. This gavea total solid amount of 337.50 g. Therefore, solids made 9% contributionto the Total solution, and the remaining 91% was made up by the liquidcomponent (Ethyl Alcohol Anhydrous).

TABLE 66 Theoretical and Actual Tablet weights at 44 mg, 46 mg, 48 mg,50 mg, 52 mg, and 54 mg weight gains for batch BUP-HBr-EA-300mg-005-5.Weight Gain (mg) Theoretical Weight (mg) Actual Weight (mg) 44.0 364.0364.9 46.0 366.0 366.3 48.0 368.0 368.5 50.0 370.0 371.7 52.0 372.0372.9 54.0 374.0 373.7

TABLE 67 Materials used in the EC coating and their quantities for batchBUP-HBr-EA-300mg-006-5. % Con- tribution Batch to Total Quantity % ofSolids Materials Solution (g) in Solution Ethocel (Ethyl Cellulose) 4.94232.03* 55.00 Standard 100 Premium Povidone USP (Kollidone 90F) 2.52118.12* 28.00 Dibutyl Sebacate 1.54 71.72* 17.00 Ethyl Alcohol Anhydrous91.0 4265.63 N/A (200 Proof) Total 100.00 4687.50 100.00 *Total solidincluded 232.03 g of Ethocel, 118.12 g of Povidone and 71.72 g ofDibutyl Sebacate. This gave a total solid amount of 421.87 g. The Solidcomponent of the coating solution made up 9% of the total solution. Theremaining 91% of the solution was made up by the Ethyl Alcohol Anhydrous(liquid component).

TABLE 68 Theoretical and Actual Tablet weights at 18 mg, 20 mg, 22 mg,24 mg, 26 mg, 28 mg, 30 mg, 32 mg, 34 mg, and 36 mg weight gains forbatch BUP-HBr-EA-150mg-006-5. Weight Gain (mg) Theoretical Weight (mg)Actual Weight (mg) 18.0 178.0 178.2 20.0 180.0 180.3 22.0 182.0 181.824.0 184.0 184.6 26.0 186.0 185.8 28.0 188.0 188.8 30.0 190.0 190.9 32.0192.0 191.6 34.0 194.0 194.1 36.0 196.0 196.7

TABLE 69 Materials used in the EC coating and their quantities for batchBUP-HBr-EA-150mg-007-5. % Con- tribution Batch to Total Quantity % ofSolids Materials Solution (g) Solution* Ethocel (Ethyl Cellulose) 4.94232.03 55.00 Standard 100 Premium Povidone USP (Kollidone 90F) 2.52118.12 28.00 PEG 4000 1.54 71.72 17.00 Ethyl Alcohol 95% USP 91.004265.63 N/A Total 100.00 4687.50 100.00 *Total Solid included 232.03 gof Ethocel, 118.12 g of Povidone and 71.72 g of PEG 4000. This gave atotal solid amount of 421.87 g.

TABLE 70 Open-dish stability studies (40 C./75% RH) on Bupropion HCl &Bupropion HBr EC Coated Tablets Open dish stability (40 C./75% RH) TestsInitial 13 Days 20 Days Bupropion HBr XL 348 mg coated EC tablets (EC-32mg WG.), Lot# Bup-HBr-XL-012-5 (EC-32 mg wg.) % Assay 101.2 99.6 99.9 %Impurities 3-CBZ 0.021 0.056 0.067 852U77 0.029 0.350 0.486 20U78/dilu0.054 0.046 0.047 827U76 ND 0.056 0.062 Total unknown 0.356 0.059 0.123Total 0.46 0.57 0.79 Bupropion HCl XL 300 mg coated EC tablets (EC, Lot#05D047) % Assay 100.4 100.2 96.2 % Impurities 3-CBZ 0.015 0.089 0.117852U77 0.041 0.337 0.378 20U78/dilu 0.038 0.046 0.045 827U76 0.023 0.0710.080 Total unknown 0.118 0.112 0.145 Total 0.24 0.66 0.77

TABLE 71 Open dish-stability studies (40 C./75% RH) on Bupropion HCl &HBr Final Coated Tablets Bupropion HBr XL 348 mg coated tablets (final 8mg wg), Wellbutrin Lot# Bup-HBr- (Bupropion XL- 012-5 (EC32 HCl) XL 300mg mg wg - tablets final 8 mg wg.) Lot# 05A116 Tests Initial 13-Days 20Days Initial 13 Days 20 Days % Assay 97.7 103.0 98.6 98.1 95.6 95.5 %Impurities 0.021 0.091 0.119 0.032 0.171 0.279 3-CBZ 852U77 0.039 0.5050.412 0.193 0.974 1.228 20U78/dilu 0.051 0.055 0.048 0.042 0.055 0.062827U76 ND 0.046 0.054 0.028 0.082 0.096 Total unknown 0.476 0.110 0.1120.083 0.033 0.06 Total (%) 0.58 0.80 0.75 0.38 1.32 1.73

TABLE 72 Average weight of excipients and weight of the API present inthe forced degradation samples for Example 8 Average weight in mgspresent in samples Component used for Forced deg study API 348 -HBr350 - HCl Precirol 162 Mannitol 413 Avicel pH 101 154 L-HPC 20 Kollidon20 Citric acid 31 Ethylcellulose 54 E45 ATBC 16

TABLE 73 BUPROPION HBr EA COATING SOLUTION FORMULATION/mg/TABLET FORPIVOTAL BATCHES Qty. Required % of Item # Material (kg) Batch Mg/tablet150 mg EA Coated Tablets - Pivotal Coating Formulation/Batch Size RE0233Ethylcellulose 4.210 4.95% 19.80 100, NF RE0067 Povidone, 2.140 2.52%10.06 USP RE0331 Polyethylene 0.435 0.51% 2.05 Glycol 4000, NF RE0103Dibutyl 0.870 1.02% 4.09 Sebacate, NF RS0010 Dehydrated 73.475 86.44% N/A Alcohol, 200 proof, USP RS0006 Ethyl Alcohol, 3.870 4.56% N/A 95%,USP COOATING SOLUTION   85 kg  100%   36 mg TOTAL (kg) Range: (38-40 mg)*RE0223 Carnauba 0.010 kg N/A 0.05 mg/tablet Wax, NF 300 mg EA CoatedTablets - Pivotal Coating Formulation/Batch Size RE0233 Ethylcellulose5.450 4.95% 23.12 100, NF RE0067 Povidone, 2.770 2.52% 11.75 USP RE0331Polyethylene 0.560 0.51% 2.38 Glycol 4000, NF RE0103 Dibutyl 1.120 1.02%4.75 Sebacate, NF RS0010 Dehydrated 95.070 86.43%  N/A Alcohol, 200proof, USP RS0006 Ethyl Alcohol, 5.030 4.57% N/A 95%, USP COATINGSOLUTION   110 kg  100%   42 mg/tablet TOTAL (kg) Range: (40-44 mg)*RE0223 Carnauba 0.010 kg N/A 0.05 mg/tablet Wax, NF Note: Whereapplicable, percentages and mg/tablet totals have been rounded to twodecimal places. *Carnauba Wax not included as part of coating solutionformulation. Trace amounts applied after completion of the coatingprocess.

Updated Stability Data at 12 Months for Bupropion.HBr FV0092 StabilityProtocol TS115

TABLE 74 ACCELERATED STABILITY PROGRAM Product: Bupropion•HBr Batch No.:D00894 Start date: 20 Dec. 2004 Temperature: 40° C. ± 2° C. FV0092 R.H.:75% ± 5% Analysis Specification time 0 3 month 6 months Descriptionwhite or almost white conform conform conform crystalline powderIdentification IR, HPLC (positive) positive positive positive Watercontent (K.F.) NMT 0.5%  0.05  0.07  0.08 Chromatographic 1) NMT 0.1% 1)n.d. 1) n.q. 1) 0.05 purity A) 2) NMT 0.1% 2) n.d. 2) n.d. 2) n.d.(HPLC) 3) NMT 0.1% 3) n.q. 3) n.q. 3) n.q. Chromatographic 4) NMT 0.1%4) 0.04 4) 0.03 4) 0.04 purity B) 5) NMT 0.1% 5) 0.04 5) 0.04 5) n.q.(HPLC) 6) NMT 0.3% 6) 0.04 6) 0.06 6) 0.02 Chromatographic Totalimpurities  0.1  0.1  0.1 purity (HPLC: A + B) NMT 0.5% Assay (HPLC)98.0-102.0% on d.b. 99.6 99.6 99.7 Impurities: 1)3′-Chloropropiophenone; 2) 3′-Chloro-2-bromopropiophenone; 3)3′-Chlorobenzoic acid; 4) 2-N-(tert-Butyl)-aminopropiophenone; 5) singleunknown impurity (each); 6) total unknown impurities (calculated fromthe sum of all impurity peak areas, also peaks below LOQ are included).Notes: n.d. = not detectable; n.q. = not quantifiable; LOQ = 0.05% forimp. 1, 2 and 3; LOQ = 0.02% for imp. 4 and 5; LOD = 0.01% for imp. 1and 3; LOD = 0.04% for imp. 2; LOD = 0.002% for imp. 4 and 5.

TABLE 75 ACCELERATED STABILITY PROGRAM Product: Bupropion•HBr Batch No.:D00895 Start date: 20 Dec. 2004 Temperature: 40° C. ± 2° C. FV0092 R.H.:75% ± 5% Analysis Specification time 0 3 month 6 months Descriptionwhite or almost white conform conform conform crystalline powderIdentification IR, HPLC (positive) positive positive positive Watercontent (K.F.) NMT 0.5%  0.04  0.07  0.07 Chromatographic 1) NMT 0.1% 1)n.d. 1) n.q. 1) 0.05 purity A) 2) NMT 0.1% 2) n.d. 2) n.d. 2) n.d.(HPLC) 3) NMT 0.1% 3) n.q. 3) 0.05 3) n.q. Chromatographic 4) NMT 0.1%4) 0.04 4) 0.03 4) 0.04 purity B) 5) NMT 0.1% 5) 0.04 5) 0.04 5) n.q.(HPLC) 6) NMT 0.3% 6) 0.04 6) 0.05 6) 0.02 Chromatographic Totalimpurities  0.1  0.1  0.1 purity (HPLC: A + B) NMT 0.5% Assay (HPLC)98.0-102.0% on d.b. 99.2 100.7 99.7 Impurities: 1)3′-Chloropropiophenone; 2) 3′-Chloro-2-bromopropiophenone; 3)3′-Chlorobenzoic acid; 4) 2-N-(tert-Butyl)-aminopropiophenone; 5) singleunknown impurity (each); 6) total unknown impurities (calculated fromthe sum of all impurity peak areas, also peaks below LOQ are included).Notes: n.d. = not detectable; n.q. = not quantifiable; LOQ = 0.05% forimp. 1, 2 and 3; LOQ = 0.02% for imp. 4 and 5; LOD = 0.01% for imp. 1and 3; LOD = 0.04% for imp. 2; LOD = 0.002% for imp. 4 and 5.

TABLE 76 ACCELERATED STABILITY PROGRAM Product: Bupropion•HBr Batch No.:D00896 Start date: 20 Dec. 2004 Temperature: 40° C. ± 2° C. FV0092 R.H.:75% ± 5% Analysis Specification time 0 3 month 6 months Descriptionwhite or almost white conform conform conform crystalline powderIdentification IR, HPLC (positive) positive positive positive Watercontent (K.F.) NMT 0.5%  0.06  0.11  0.04 Chromatographic 1) NMT 0.1% 1)n.d. 1) n.q. 1) 0.05 purity A) 2) NMT 0.1% 2) n.d. 2) n.d. 2) n.d.(HPLC) 3) NMT 0.1% 3) n.q. 3) n.q. 3) n.q. Chromatographic 4) NMT 0.1%4) 0.04 4) 0.03 4) 0.04 purity B) 5) NMT 0.1% 5) 0.05 5) 0.04 5) n.q.(HPLC) 6) NMT 0.3% 6) 0.05 6) 0.05 6) n.q. Chromatographic Totalimpurities  0.1  0.1  0.1 purity (HPLC: A + B) NMT 0.5% Assay (HPLC)98.0-102.0% on d.b. 99.3 100.0 100.4 Impurities: 1)3′-Chloropropiophenone; 2) 3′-Chloro-2-bromopropiophenone; 3)3′-Chlorobenzoic acid; 4) 2-N-(tert-Butyl)-aminopropiophenone; 5) singleunknown impurity (each); 6) total unknown impurities (calculated fromthe sum of all impurity peak areas, also peaks below LOQ are included).Notes: n.d. = not detectable; n.q. = not quantifiable; LOQ = 0.05% forimp. 1, 2 and 3; LOQ = 0.02% for imp. 4 and 5; LOD = 0.01% for imp. 1and 3; LOD = 0.04% for imp. 2; LOD = 0.002% for imp. 4 and 5.

TABLE 77 SHELF LIFE STABILITY PROGRAM Product: Bupropion.HBr Batch No.:D00894 Start date: 20/12/04 Temperature: 25° C. ± 2 ° C.; FV0092Relative Humidity: 60% ± 5% Analysis Specification time 0 3 months 6months 9 months 12 months 18 months 24 months 36 months Descriptionwhite or almost white conform conform conform conform conformcrystalline powder Identification IR, HPLC (positive) positive positivepositive positive positive Water content (K.F.) NMT 0.5% 0.05 0.05 0.060.05 0.05 Chromatographic 1) NMT 0.1% 1) n.d. 1) n.q. 1) 0.05 1) n.q. 1)n.d. 1) 1) 1) purity A) (HPLC) 2) NMT 0.1% 2) n.d. 2) n.d. 2) n.d. 2)n.d. 2) n.d. 2) 2) 2) 3) NMT 0.1% 3) n.q. 3) n.q. 3) n.q. 3) n.q. 3)0.05 3) 3) 3) Chromatographic 4) NMT 0.1% 4) 0.04 4) 0.03 4) 0.05 4)n.d. 4) 0.05 4) 4) 4) purity B) (HPLC) 5) NMT 0.1% 5) 0.04 5) 0.04 5)n.q. 5) n.q. 5) 0.05 5) 5) 5) 6) NMT 0.3% 6) 0.04 6) 0.05 6) 0.02 6)n.q. 6) 0.07 6) 6) 6) Chromatographic Total impurities 0.1 0.1 0.1 n.q.0.2 purity (HPLC: A + B) NMT 0.5% Assay (HPLC) 98.0-102.0% on d.b. 99.699.4 100.2 99.5 99.6 Microbial cont. total microbial not not not not<100 ufc/g not count <1000 cfu/g applied applied applied applied <100ufc/g applied moulds and yeast <100 cfu/g Impurities: 1)3′-Chloropropiophenone; 2) 3′-Chloro-2-bromopropiophenone; 3)3′-Chlorobenzoic acid; 4) 2-N-(tert-Butyl)-aminopropiophenone; 5) singleunknown impurity (each); 6) total unknown impurities (calculated fromthe sum of all impurity peak areas, also peaks below LOQ are included).Notes: n.d. = not detectable; n.q. = not quantifiable; LOQ = 0. 05% forimp. 1, 2 and 3; LOQ = 0.02% for imp. 4 and 5; LOD = 0.01% for imp. 1and 3; LOD = 0.04% for imp. 2; LOD = 0.002% for imp. 4 and 5.

TABLE 78 SHELF LIFE STABILITY PROGRAM Product: Bupropion.HBr Batch No.:D00895 Start date: 20/12/04 Temperature: 25° C. ± 2 ° C.; FV0092Relative Humidity: 60% ± 5% Analysis Specification time 0 3 months 6months 9 months 12 months 18 months 24 months 36 months Descriptionwhite or almost white conform conform conform conform conformcrystalline powder Identification IR, HPLC (positive) positive positivepositive positive positive Water content (K.F.) NMT 0.5% 0.04 0.04 0.050.05 0.04 Chromatographic 1) NMT 0.1% 1) n.d. 1) n.q. 1) 0.05 1) n.q. 1)n.d. 1) 1) 1) purity A) (HPLC) 2) NMT 0.1% 2) n.d. 2) n.d. 2) n.d. 2)n.d. 2) n.d. 2) 2) 2) 3) NMT 0.1% 3) n.q. 3) n.q. 3) n.q. 3) n.q. 3)0.05 3) 3) 3) Chromatographic 4) NMT 0.1% 4) 0.04 4) 0.03 4) 0.05 4) n.d4) 0.05 4) 4) 4) purity B) (HPLC) 5) NMT 0.1% 5) 0.04 5) 0.04 5) n.q. 5)n.q. 5) 0.07 5) 5) 5) 6) NMT 0.3% 6) 0.04 6) 0.05 6) 0.02 6) n.q. 6)0.07 6) 6) 6) Chromatographic Total impurities 0.1 0.1 0.1 n.q. 0.2purity (HPLC: A + B) NMT 0.5% Assay (HPLC) 98.0-102.0% on d.b. 99.2 99.5100.1 99.4 99.4 Microbial cont. total microbial not not not not <100ufc/g not count <1000 cfu/g applied applied applied applied <100 ufc/gapplied moulds and yeast <100 cfu/g Impurities: 1)3′-Chloropropiophenone; 2) 3′-Chloro-2-bromopropiophenone; 3)3′-Chlorobenzoic acid; 4) 2-N-(tert-Butyl)-aminopropiophenone; 5) singleunknown impurity (each); 6) total unknown impurities (calculated fromthe sum of all impurity peak areas, also peaks below LOQ are included).Notes: n.d. = not detectable; n.q. = not quantifiable; LOQ = 0. 05% forimp. 1, 2 and 3; LOQ = 0.02% for imp. 4 and 5; LOD = 0.01% for imp. 1and 3; LOD = 0.04% for imp. 2; LOD = 0.002% for imp. 4 and 5.

TABLE 79 SHELF LIFE STABILITY PROGRAM Product: Bupropion.HBr Batch No.:D00896 Start date: 20/12/04 Temperature: 25° C. ± 2 ° C.; FV0092Relative Humidity: 60% ± 5% Analysis Specification time 0 3 months 6months 9 months 12 months 18 months 24 months 36 months Descriptionwhite or almost white conform conform conform conform conformcrystalline powder Identification IR, HPLC (positive) positive positivepositive positive positive Water content (K.F.) NMT 0.5% 0.06 0.04 0.040.04 0.03 Chromatographic 1) NMT 0.1% 1) n.d. 1) n.q. 1) 0.05 1) n.q. 1)n.d. 1) 1) 1) purity A) (HPLC) 2) NMT 0.1% 2) n.d. 2) n.d. 2) n.d. 2)n.d. 2) n.d. 2) 2) 2) 3) NMT 0.1% 3) n.q. 3) n.q. 3) n.q. 3) n.q. 3)n.q. 3) 3) 3) Chromatographic 4) NMT 0.1% 4) 0.04 4) 0.03 4) 0.04 4) n.d4) 0.05 4) 4) 4) purity B) (HPLC) 5) NMT 0.1% 5) 0.05 5) 0.04 5) n.q. 5)n.q. 5) 0.07 5) 5) 5) 6) NMT 0.3% 6) 0.05 6) 0.05 6) n.q. 6) n.q. 6)0.07 6) 6) 6) Chromatographic Total impurities 0.1 0.1 0.1 n.q. 0.1purity (HPLC: A + B) NMT 0.5% Assay (HPLC) 98.0-102.0% on d.b. 99.3 99.4100.5 99.4 100.3 Microbial cont. total microbial not not not not <100ufc/g not count <1000 cfu/g applied applied applied applied <100 ufc/gapplied moulds and yeast <100 cfu/g Impurities: 1)3′-Chloropropiophenone; 2) 3′-Chloro-2-bromopropiophenone; 3)3′-Chlorobenzoic acid ; 4) 2-N-(tert-Butyl)-aminopropiophenone; 5)single unknown impurity (each); 6) total unknown impurities (calculatedfrom the sum of all impurity peak areas, also peaks below LOQ areincluded). Notes: n.d. = not detectable; n.q. = not quantifiable; LOQ =0.05% for imp. 1, 2 and 3; LOQ = 0.02% for imp. 4 and 5; LOD = 0.01% forimp. 1 and 3; LOD = 0.04% for imp. 2; LOD = 0.002% for imp. 4 and 5.

TABLE 80 Bupropion Hydrobromide Polymorphs Table Cosolvent Yield K. F.Trial Solvent (voll.) (voll.) (%) Form (%) Notes 085 IPA + HBr gas I0.07 Standard procedure 097 Water 2 / 72 I 0.06 098A Methanol 2.4 / II0.13 098B Acetone 17 water 0.7 24 II 0.16 099 Ethanol abs. 4.8 / 56 III0.12 100 IPA 15.1 / 77 I 0.11 102 AcOi-Pr 20 MeOH 3.6 26 I 0.25 108Acetonitrile 20 / 70 I 0.14 109 Dichloromethane 30 / 25 II 0.21 110Water 2 HBr 48% 1 83 I 0.12 111 IPA 6 HBr 48% 1 69 I 0.32 112 MTBE 10MeOH 3 67 I 0.18 113 Toluene 10 MeOH 1.25 40 II 0.39 114 DMC 10 MeOH1.75 67 II 0.17 115 t-BuOH 20 Water 0.55 74 I 0.15 116 Form I inrotavapor 100° C. 24 h I 0.45 117 IPA 10 Water 0.125 88 I 0.32 118Toluene 10 MeOH 1.15 99 I 0.16 119 IPA 8 MeOH 1.32 83 I 0.47 120Sec-BuOH 25 / 89 I 0.13 122 Water 8 / I 1.3 Spray dried

TABLE 81 Polyethoxylated Fatty Acids PEG-Fatty Acid MonoesterSurfactants Compound Commercial Product (Supplier) HLB PEG 4-100 CrodetL series (Croda) >9 monolaurate PEG 4-100 Crodet O series (Croda) >8monooleate PEG 4-100 Crodet S series (Croda), >6 monostearate MyrjSeries (Atlas/ICI) PEG 400 distearate Cithrol 4DS series (Croda) >10 PEG100, 200, 300 Cithrol ML series (Croda) >10 monolaurate PEG 100, 200,300 Cithrol MO series (Croda) >10 monooleate PEG 400 dioleate Cithrol4DO series (Croda) >10 PEG 400-1000 Cithrol MS series (Croda) >10monostearate PEG-1 stearate Nikkol MYS-IEX (Nikko), 2 Coster KI (Condea)PEG-2 stearate Nikkol MYS-2 (Nikko) 4 PEG-2 oleate Nikkol MYO-2 (Nikko)4.5 PEG-4 laurate Mapeg ® 200 ML (PPG), 9.3 Kessco ® PEG 200 ML(Stepan), LIPOPEG 2 L (LIPO Chem.) PEG-4 oleate Mapeg ® 200 MO (PPG),8.3 Kessco ® PEG200 MO (Stepan), PEG-4 stearate Kesseo ® PEG 200 MS(Stepan), 6.5 Hodag 20 S (Calgene), Nikkol MYS-4 (Nikko) PEG-5 stearateNikkol TMGS-5 (Nikko) 9.5 PEG-5 oleate Nikkol TMGO-5 (Nikko) 9.5 PEG-6oleate Algon OL 60 (Auschem SpA), 8.5 Kessco ® PEG 300 MO (Stepan),Nikkol MYO-6 (Nikko), Emulgante A6 (Condea) PEG-7 oleate Algon OL 70(Auschem SpA) 10.4 PEG-6 laurate Kessco ® PEG300 ML (Stepan) 11.4 PEG-7laurate Lauridac 7 (Condea) 13 PEG-6 stearate Kessco ® PEG300 MS(Stepan) 9.7 PEG-8 laurate Mapeg ® 400 ML (PPG), 13 LIPOPEG 4DL(LipoChem.) PEG-8 oleate Mapeg ® 400 MO (PPG), 12 Emulgante A8 (Condea);Kessco PEG 400 MO (Stepan) PEG-8 stearate Mapeg ® 400 MS (PPG), 12 Myrj45 PEG-9 oleate Emulgante A9 (Condea) >10 PEG-9 stearate Cremophor 59(BASF) >10 PEG-10 laurate Nikkol MYL-10 (Nikko), 13 Lauridac 10 (Croda)PEG-10 oleate Nikkol MYO-10 (Nikko) 11 PEG-10 stearate Nikkol MYS-10(Nikko), 11 Coster K100 (Condea) PEG-12 laurate Kessco ® PEG 600 ML(Stepan) 15 PEG-12 oleate Kessco ® PEG 600MO (Stepan) 14 PEG-12ricinoleate (CAS #9004-97-1) >10 PEG-12 stearate Mapeg ® 600 MS (PPG),14 Kessco ® PEG 600MS (Stepan) PEG-15 stearate Nikkol TMGS-15 (Nikko),14 Koster K15 (Condea) PEG-15 oleate Nikkol TMGO-15 (Nikko) 15 PEG-20laurate Kessco ® PEG 1000 ML (Stepan) 17 PEG-20 oleate Kessco ® PEG 1000MO (Stepan) 15 PEG-20 stearate Mapeg ® 1000 MS (PPG), 16 Kessco ® PEG1000 MS (Stepan), Myrj 49 PEG-25 stearate Nikkol MYS-25 (Nikko) 15PEG-32 laurate Kessco ® PEG 1540 ML (Stepan) 16 PEG-32 oleate Kessco ®PEG 1540 MO (Stepan) 17 PEG-32 stearate Kessco ® PEG 1540 MS (Stepan) 17PEG-30 stearate Myrj 51 >10 PEG-40 laurate Crodet L40 (Croda) 17.9PEG-40 oleate Crodet O40 (Croda) 17.4 PEG-40 stearate Myrj 52, Emerest ®2715 (Henkel), >10 Nikkol MYS-40 (Nikko) PEG-45 stearate Nikkol MYS-45(Nikko) 18 PEG-50 stearate Myrj 53 >10 PEG-55 stearate Nikkol MYS-55(Nikko) 18 PEG-100 oleate Crodet 0-100 (Croda) 18.8 PEG-100 stearateMyrj 59, Arlacel 165 (ICI) 19 PEG-200 oleate Albunol 200 MO (TaiwanSurf.) >10 PEG-400 oleate LACTOMUL (Henkel), >10 Albunol 400 MO (TaiwanSurf.) PEG-600 oleate Albunol 600 MO (Taiwan Surf) >10

Although polyethylene glycol (PEG) itself does not function as asurfactant, a variety of PEG-fatty acid esters have useful surfactantproperties. Examples of polyethoxylated fatty acid monoester surfactantscommercially available are shown here in Table 81.

TABLE 82 PEG-Fatty Acid Diesters PEG-Fatty Acid Diester SurfactantsCompound Commercial Product (Supplier) HLB PEG-4 dilaurate Mapeg ® 200DL (PPG), 7 Kessco ® PEG 200 DL (Stepan), 6 LIPOPEG 2-DL (Lipo Chem.)PEG-4 dioleate Mapeg ® 200 DO (PPG), 6 PEG-4 distearate Kessco ® 200 DS(Stepan) 5 PEG-6 dilaurate Kessco ® PEG 300 DL (Stepan) 9.8 PEG-6dioleate Kessco ® PEG 300 DO (Stepan) 7.2 PEG-6 distearate Kessco ® PEG300 DS (Stepan) 6.5 PEG-8 dilaurate Mapeg ® 400 DL (PPG), 11 Kessco ®PEG 400 DL (Stepan), LIPOPEG 4 DL (Lipo Chem.) PEG-8 dioleate Mapeg ®400 DO (PPG), 8.8 Kessco ® PEG 400 DO (Stepan), LIPOPEG 4 DO(Lipo Chem.)PEG-8 distearate Mapeg ® 400 DS (PPG), 11 CDS 400 (Nikkol) PEG-10dipalmitate Polyaldo 2PKFG >10 PEG-12 dilaurate Kessco ® PEG 600 DL(Stepan) 11.7 PEG-12 distearate Kessco ® PEG 600 DS (Stepan) 10.7 PEG-12dioleate Mapeg ® 600 DO (PPG), 10 Kessco ® 600 DO(Stepan) PEG-20dilaurate Kessco ® PEG 1000 DL (Stepan) 15 PEG-20 dioleate Kessco ® PEG1000 DO (Stepan) 13 PEG-20 distearate Kessco ® PEG 1000 DS (Stepan) 12PEG-32 dilaurate Kessco ® PEG 1540 DL (Stepan) 16 PEG-32 dioleateKessco ® PEG 1540 DO (Stepan) 15 PEG-32 distearate Kessco ® PEG 1540 DS(Stepan) 15 PEG-400 dioleate Cithrol 4DO series (Croda) >10 PEG-400distearate Cithrol 4DS series (Croda) >10

Polyethylene glycol (PEG) fatty acid diesters are also suitable for useas surfactants in the compositions of the present invention.Representative PEG-fatty acid diesters are shown here in Table 82.

TABLE 83 PEG-Fatty Acid Mono- and Di-ester Mixtures PEG-Fatty AcidMono-and Diester Mixtures Compound Commercial Product (Supplier) PEG4-150 mono, Kessco ® PEG 200-6000 mono, dilaurate (Stepan) dilaurate PEG4-150 mono, Kessco ® PEG 200-6000 mono, dioteate (Stepan) dioleate PEG4-150 mono, Kessco ® 200-6000 mono, distearate (Stepan) distearate

In general, mixtures of surfactants are also useful in the presentinvention, including mixtures of two or more commercial surfactantproducts. Several PEG-fatty acid esters are marketed commercially asmixtures or mono- and diesters. Representative surfactant mixtures areshown here in Table 83.

TABLE 84 Polyethylene Glycol Glycerol Fatty Acid Esters PEG GlycerolFatty Acid Esters Compound Commercial Product (Supplier) HLB PEG-20glyceryl Tagat ® L (Goldschmidt) 16 laurate PEG-30 glyceryl Tagat ® L2(Goldschmidt) 16 laurate PEG-15 glyceryl Glycerox L series (Croda) 15laurate PEG-40 glyceryl Glycerox L series (Croda) 15 laurate PEG-20glyceryl Capmul ® EMG (ABITEC), 13 stearate Aldo ® MS-20 KFG (Lonza)PEG-20 glyceryl Tagat ® O (Goldschmidt) >10 oleate PEG-30 glycerylTagat ® O2 (Goldschmidt) >10 oleate

Suitable PEG glycerol fatty acid esters are shown here in Table 84.

TABLE 85 Alcohol--Oil Transesterification Products TransesterificationProducts of Oils and Alcohols Compound Commercial Product (Supplier) HLBPEG-3 castor oil Nikkol CO-3 (Nikko) 3 PEG-5, 9, and 16 ACCONON CAseries (ABITEC) 6-7 castor oil PEG-20 castor oil Emalex C-20 (NihonEmulsion), 11 Nikkol CO-20 TX (Nikko) PEG-23 castor oil EmulganteEL23 >10 PEG-30 castor oil Emalex C-30 (Nihon Emulsion), 11 Alkamuls ®EL 620 (Rhone- Poulenc), Incrocas 30 (Croda) PEG-35 castor oil CremophorEL and EL-P (BASF), Emulphor EL, Incrocas-35 (Croda), Emulgin RO 35(Henkel) PEG-38 castor oil Emulgante EL 65 (Condea) PEG-40 castor oilEmalex C-40 (Nihon Emulsion), 13 Alkamuls ® EL 719 (Rhone- Poulenc)PEG-50 castor oil Emalex C-50 (Nihon Emulsion) 14 PEG-56 castor oilEumulgin ® PRT 56 (Pulcra SA) >10 PEG-60 castor oil Nikkol CO-60TX(Nikko) 14 PEG-100 castor oil Thornley >10 PEG-200 castor oil Eumulgin ®PRT 200 (Pulcra SA) >10 PEG-5 hydrogenated Nikkol HCO-5 (Nikko) 6 castoroil PEG-7 hydrogenated Simusol ® 989 (Seppic), 6 castor oil CremophorWO7 (BASF) PEG-10 hydrogenated Nikkol HCO-10 (Nikko) 6.5 castor oilPEG-20 hydrogenated Nikkol HCO-20 (Nikko) 11 castor oil PEG-25hydrogenated Simulsol ® 1292 (Seppic), 11 castor oil Cerex ELS 250(Auschem SpA) PEG-30 hydrogenated Nikkol HCO-30 (Nikko) 11 castor oilPEG-40 hydrogenated Cremophor RH 40 (BASF), 13 castor oil Croduret(Croda), Emulgin HRE 40 (Henkel) PEG-45 hydrogenated Cerex ELS 450(Auschem Spa) 14 castor oil PEG-50 hydrogenated Emalex HC-50 (NihonEmulsion) 14 castor oil PEG-60 hydrogenated Nikkol HCO-60 (Nikko), 15castor oil Cremophor RH 60 (BASF) PEG-80 hydrogenated Nikkol HCO-80(Nikko) 15 castor oil PEG-100 Nikkol HCO-100 (Nikko) 17 hydrogenatedcastor oil PEG-6 corn oil Labrafil ® M 2125 CS (Gattefosse) 4 PEG-6almond oil Labrafil ® M 1966 CS (Gattefosse) 4 PEG-6 apricot kernelLabrafil ® M 1944 CS (Gattefosse) 4 oil PEG-6 olive oil Labrafil ® M1980 CS (Gattefosse) 4 PEG-6 peanut oil Labrafil ® M 1969 CS(Gattefosse) 4 PEG-6 hydrogenated Labrafil ® M 2130 BS (Gattefosse) 4palm kernel oil PEG-6 palm kernel oil Labrafil ® M 2130 CS (Gattefosse)4 PEG-6 triolein Labrafil ® M 2735 CS (Gattefosse) 4 PEG-8 corn oilLabrafil ® WL 2609 BS (Gattefosse) 6-7 PEG-20 corn Crovol M40 (Croda) 10glycerides PEG-20 almond Crovol A40 (Croda) 10 glycerides PEG-25trioleate TAGAT ® TO (Goldschmidt) 11 PEG-40 palm kernel CrovolPK-70 >10 oil PEG-60 corn Crovol M70(Croda) 15 glycerides PEG-60 almondCrovol A70 (Croda) 15 glycerides PEG-4 caprylic/capric Labrafac ® Hydro(Gattefosse), 4-5 triglyceride PEG-8 caprylic/capric Labrasol(Gattefosse), >10 glycerides Labrafac CM 10 (Gattefosse) PEG-6caprylic/capric SOFTIGEN ® 767 (Huls), 19 glycerides Glycerox 767(Croda) Lauroyl macrogol-32 GELUCIRE 44/14 (Gattefosse) 14 glycerideStearoyl macrogol GELUCIRE 50/13 (Gattefosse) 13 glyceride Mono, di,tri, SorbitoGlyceride (Gattefosse) <10 tetra esters of vegetable oilsand sorbitol Pentaerythrityl Crodamol PTIS (Croda) <10 tetraisostearatePentaerythrityl Albunol DS (Taiwan Surf.) <10 distearate PentaerythritylLiponate PO-4 (Lipo Chem.) <10 tetraoleate Pentaerythrityl Liponate PS-4(Lipo Chem.) <10 tetrastearate Pentaerythrityl Liponate PE-810 (LipoChem.), <10 tetracaprylate/ Crodamol PTC (Croda) tetracapratePentaerythrityl Nikkol Pentarate 408 (Nikko) tetraoctanoate

A large number of surfactants of different degrees of lipophilicity orhydrophilicity can be prepared by reaction of alcohols or polyalcoholswith a variety of natural and/or hydrogenated oils. In certainembodiments, the oils used are castor oil or hydrogenated castor oil oran edible vegetable oil such as corn oil, olive oil, peanut oil, palmkernel oil, apricot kernel oil, or almond oil. Examples of alcoholsinclude glycerol, propylene glycol, ethylene glycol, polyethyleneglycol, sorbitol, and pentaerythritol. Representative surfactants ofthis class suitable for use in the present invention are shown here inTable 85.

TABLE 86 Polyglycerized Fatty Acids Polyglycerized Fatty Acids CompoundCommercial Product (Supplier) HLB Polyglyceryl-2 stearate Nikkol DGMS(Nikko) 5-7 Polyglyceryl-2 oleate Nikkol DGMO (Nikko) 5-7 Polyglyceryl-2Nikkol DGMIS (Nikko) 5-7 isostearate Polyglyceryl-3 oleate Caprol ® 3G0(ABITEC), 6.5 Drewpol 3-1-O (Stepan) Polyglyceryl-4 oleate NikkolTetraglyn 1-O (Nikko) 5-7 Polyglyceryl-4 stearate Nikkol Tetraglyn 1-S(Nikko) 5-6 Polyglyceryl-6 oleate Drewpol 6-1-O (Stepan), 9 NikkolHexaglyn 1-O (Nikko) Polyglyceryl-10 Nikkol Decaglyn 1-L (Nikko) 15laurate Polyglyceryl-10 oleate Nikkol Decaglyn 1-O (Nikko) 14Polyglyceryl-10 Nikkol Decaglyn 1-S (Nikko) 12 stearate Polyglyceryl-6Nikkol Hexaglyn PR-15 (Nikko) ricinoleate Polyglyceryl-10 NikkolDecaglyn I-LN (Nikko) 12 linoleate Polyglyceryl-6 Nikkol Hexaglyn S-O(Nikko) <10 pentaoleate Polyglyceryl-3 Cremophor G032 (BASF) <10dioleate Polyglyceryl-3 Cremophor GS32 (BASF) <10 distearatePolyglyceryl-4 Nikkol Tetraglyn 5-O (Nikko) <10 pentaoleatePolyglyceryl-6 Caprol ® 6G20 (ABITEC); 8.5 dioleate Hodag PGO-62(Calgene), PLUROL OLEIQUE CC 497 (Gattefosse) Polyglyceryl-2 Nikkol DGDO(Nikko) 7 dioleate Polyglyceryl-10 Nikkol Decaglyn 3-O (Nikko) 7trioleate Polyglyceryl-10 Nikkol Decaglyn 5-O (Nikko) 3.5 pentaoleatePolyglyceryl-10 Nikkol Decagtyn 7-O (Nikko) 3 septaoleatePolyglyceryl-10 Caprol ® 10G40 (ABITEC); 6.2 tetraoleate Hodag PGO-62(CALGENE), Drewpol 10-4-O (Stepan) Polyglyceryl-10 Nikkol Decaglyn 10-IS(Nikko) <10 decaisostearate Polyglyceryl-10 Drewpol 10-10-O (Stepan),3.5 decaoleate Caprol 10G10O (ABITEC), Nikkol Decaglyn 10-OPolyglyceryl-10 mono, Caprol ® PGE 860 (ABITEC) 11 dioleate PolyglycerylPolymuls (Henkel)  3-20 polyricinoIeate

Polyglycerol esters of fatty acids are also suitable surfactants for thepresent invention. Examples of suitable polyglyceryl esters are shownhere in Table 86.

TABLE 87 Propylene Glycol Fatty Acid Esters Propylene Glycol Fatty AcidEsters Compound Commercial Product (Supplier) HLB Propylene glycolCapryol 90 (Gattefosse), <10 monocaprylate Nikkol Sefsol 218 (Nikko)Propylene glycol Lauroglycol 90 (Gattefosse), <10 monolaurateLauroglycol FCC (Gattefosse) Propylene glycol Lutrol OP2000 (BASF) <10oleate Propylene glycol Mirpyl <10 myristate Propylene glycol ADMPGME-03 (ADM), 3-4 monostearate LIPO PGMS (Lipo Chem.), Aldo ® PGHMS(Lonza) Propylene glycol <10 hydroxy stearate Propylene glycol PROPYMULS(Henkel) <10 ricinoleate Propylene glycol <10 isostearate Propyleneglycol Myverol P-06 (Eastman) <10 monooleate Propylene glycol Captex ®200 (ABITEC), >6 dicaprylate/dicaprate Miglyol ® 840 (Huls), Neobee ®M-20 (Stepan) Propylene glycol Captex ® 800 (ABITEC) dioctanoatePropylene glycol LABRAFAC >6 caprylate/caprate PG (Gattefosse) Propyleneglycol >6 dilaurate Propylene glycol Kessco ® PGDS (Stepan) >6distearate Propylene glycol Nikkol Sefsol 228 (Nikko) >6 dicaprylatePropylene glycol Nikkol PDD (Nikko) >6 dicaprate

Esters of propylene glycol and fatty acids are suitable surfactants foruse in the present invention. Examples of surfactants of this class aregiven here in Table 87.

TABLE 88 Mixtures of Propylene Glycol Esters--Glycerol EstersGlycerol/Propylene Glycol Fatty Acid Esters Compound Commercial Product(Supplier) HLB Oleic ATMOS 300, ARLACEL 186 (ICI) 3-4 Stearic ATMOS 1503-4

In general, mixtures of surfactants are also suitable for use in thepresent invention. In particular, mixtures of propylene glycol fattyacid esters and glycerol fatty acid esters are suitable and arecommercially available. Examples of these surfactants are shown here inTable 88.

TABLE 89 Mono- and Diglycerides Mono- and Diglyceride SurfactantsCompound Commercial Product (Supplier) HLB Monopalmitolein (Larodan) <10(C16:1) Monoelaidin (Larodan) <10 (C18:1) Monocaproin (Larodan) <10 (C6)Monocaprylin (Larodan) <10 Monocaprin (Larodan) <10 Monolaurin (Larodan)<10 Glyceryl Nikkol MGM (Nikko) 3-4 monomyristate (C14) Glycerylmonooleate PECEOL (Gattefosse), Hodag 3-4 (C18:1) GMO-D, Nikkol MGO(Nikko) Glyceryl monooleate RYLO series (Danisco), 3-4 DIMODAN series(Danisco), EMULDAN (Danisco), ALDO ® MOFG (Lonza), Kessco GMO (Stepan),MONOMULS ® series (Henkel), TEGIN O, DREWMULSE GMO (Stepan), Atlas G-695(ICI), GMOrphic 80 (Eastman), ADM DMG-40, 70, and 100 (ADM), Myverol(Eastman) Glycerol monooleate/ OLICINE (Gattefosse) 3-4 linoleateGlycerol Maisine (Gattefosse), 3-4 monolinoleate MYVEROL 18-92, Myverol18-06 (Eastman) Glyceryl ricinoleate Softigen ® 701 (Huls), 6 HODAGGMR-D (Calgene), ALDO ® MR (Lonza) Glyceryl monolaurate ALDO ® MLD(Lonza), 6.8 Hodag GML (Calgene) Glycerol Emalex GMS-P (Nihon) 4monopalmitate Glycerol monostearate Capmul ® GMS. (ABITEC), 5-9 Myvaplex(Eastman), IMWITOR ® 191 (Huls), CUTINA GMS, Aldo ® MS (Lonza), NikkolMGS series (Nikko) Glyceryl mono-, Capmul ® GMO-K (ABITEC) <10 dioleateGlyceryl CUTINA MD-A, ESTAGEL-G18 <10 palmitic/stearic Glyceryl acetateLamegin ® EE (Grunau GmbH) <10 Glyceryl laurate Inwitor ® 312 (Huls), 4Monomuls ® 90-45 (Grunau GmbH), Aldo ® MLD (Lonza) Glyceryl citrate/Imwitor ® 375 (Huls) <10 lactate/oleate/ linoieate Glyceryl caprylateImwitor ® 308 (Huls), 5-6 Capmul ® MCMC8 (ABITEC) Glyceryl Capmul ® MCM(ABITEC) 5-6 caprylate/caprate Caprylic acid mono, Imwitor ® 988 (Huls)5-6 diglycerides Caprylic/capric Imwitor ® 742 (Huls) <10 glyceridesMono-and diacetylated Myvacet ® 9-45, 3.8-4   monoglycerides Myvacet ®9-40, Myvacet ® 9-08 (Eastman), Lamegin ® (Grunau) Glyceryl Aldo ® MS,Arlacel 129 4.4 monostearate (ICI), LIPO GMS (Lipo Chem.), Imwitor ® 191(Huls), Myvaplex (Eastman) Lactic acid esters LAMEGIN GLP (Henkel) <10of mono, diglycerides Dicaproin (C6) (Larodan) <10 Dicaprin (C10)(Larodan) <10 Dioctanoin (C8) (Larodan) <10 Dimyristin (C14) (Larodan)<10 Dipalmitin (C16) (Larodan) Distearin (Larodan) <10 Glyceryldilaurate Capmul ® GDL (ABITEC) 3-4 (C12) Glyceryl dioleate Capmul ® GDO(ABITEC) 3-4 Glycerol esters of GELUCIRE 39/01 (Gattefosse), 1 fattyacids GELUCIRE 43/01 (Gattefosse) 6 GELUCIRE 37/06 (Gattefosse)Dipalmitolein (C16:1) (Larodan) <10 1,2 and 1,3-diolein (C18:1)Dielaidin (C18:1) (Larodan) <10 Dilinolein (C18:2) (Larodan) <10

Another class of surfactants is the class of mono- and diglycerides.These surfactants are generally lipophilic. Examples of thesesurfactants are given here in Table 89.

TABLE 90 Sterol and Sterol Derivatives Sterol and Sterol DerivativeSurfactants Compound Commercial Product (Supplier) HLB Cholesterol,sitosterol, <10 lanosterol PEG-24 cholesterol Solulan C-24(Amerchol) >10 ether PEG-30 cholestanol Nikkol DHC (Nikko) >10Phytosterol GENEROL series (Henkel) <10 PEG-25 phyto sterol NikkolBPSH-25 (Nikko) >10 PEG-5 soya sterol Nikkol BPS-S (Nikko) <10 PEG-10soya sterol Nikkol BPS-10 (Nikko) <10 PEG-20 soya sterol Nikkol BPS-20(Nikko) <10 PEG-30 soya sterol Nikkol BPS-30 (Nikko) >10

Sterols and derivatives of sterols are suitable surfactants for use inthe present invention. These surfactants can be hydrophilic orlipophilic. Examples of surfactants of this class are shown here inTable 90.

TABLE 91 Polyethylene Glycol Sorbitan Fatty Acid Esters PEG-SorbitanFatty Acid Esters Compound Commercial Product (Supplier) HLB PEG-10sorbitan Liposorb L-10 (Lipo Chem.) >10 laurate PEG-20 sorbitan Tween-20(Atlas/ICI), Crillet 1 17 monolaurate (Croda), DACOL MLS 20 (Condea)PEG-4 sorbitan Tween-21 (Atlas/ICI), Crillet 11 13 monolaurate (Croda)PEG-80 sorbitan Hodag PSML-80 (Calgene); T-Maz 28 >10 monolaurate PEG-6sorbitan Nikkol GL-1 (Nikko) 16 monolaurate PEG-20 sorbitan Tween-40(Atlas/ICI), Crillet 2 16 monopalmitate (Croda) PEG-20 sorbitan Tween-60(Atlas/ICI), Crillet 3 15 monostearate (Croda) PEG-4 sorbitan Tween-61(Atlas/ICI), Crillet 31 9.6 monostearate (Croda) PEG-8 sorbitan DACOLMSS (Condea) >10 monostearate PBG-6 sorbitan Nikkol TS106 (Nikko) 11monostearate PEG-20 sorbitan Tween-65 (Atlas/ICI), Crillet 35 11tristearate (Croda) PEG-6 sorbitan Nikkol GS-6 (Nikko) 3 tetrastearatePEG-60 sorbitan Nikkol GS-460 (Nikko) 13 tetrastearate PEG-5 sorbitanTween-81 (Atlas/ICI), Crillet 41 10 monooleate (Croda) PEG-6 sorbitanNikkol TO-106 (Nikko) 10 monooleate PEG-20 sorbitan Tween-80(Atlas/ICI), Crillet 4 15 monooleate (Croda) PEG-40 sorbitan Emalex ET8040, (Nihon Emulsion) 18 oleate PEG-20 sorbitan Tween-85 (Atlas/ICI),Crillet 45 11 trioleate (Croda) PEG-6 sorbitan Nikkol GO-4 (Nikko) 8.5tetraoleate PEG-30 sorbitan Nikkol GO-430 (Nikko) 12 tetraoleate PEG-40sorbitan Nikkol GO-440 (Nikko) 13 tetraoleate PEG-20 sorbitan Tween-120(Atlas/ICI), Crillet 6 >10 monoisostearate (Croda) PEG sorbitol AtlasG-1086 (ICI) 10 hexaoleate PEG-6 sorbitol Nikkol GS-6 (Nikko) 3hexastearate

A variety of PEG-sorbitan fatty acid esters are available and aresuitable for use as surfactants in the present invention. In general,these surfactants are hydrophilic, although several lipophilicsurfactants of this class can be used. Examples of these surfactants areshown here in Table 91.

TABLE 92 Polyethylene Glycol Alkyl Ethers Polyethylene Glycol AlkylEthers Compound Commercial Product (Suppler) HLB PEG-2 oleyl ether, Brij92/93 (Atlas/ICI) 4.9 oleth-2 PEG-3 oleyl ether, Volpo 3 (Croda) <10oleth-3 PEG-5 oleyl ether, Volpo 5 (Croda) <10 oleth-5 PEG-10 oleylether, Volpo 10 (Croda), Brij 96/97 12 oleth-10 (Atlas/ICI) PEG-20 oleylether, Volpo 20 (Croda), Brij 98/99 15 oleth-20 (Atlas/ICI) PEG-4 laurylether, Brij 30 (Atlas/ICI) 9.7 laureth-4 PEG-9 lauryl ether >10 PEG-23lauryl ether, Brij 35 (Atlas/ICI) 17 *laureth-23 PEG-2 cetyl ether Brij52 (ICI) 5.3 PEG-10 cetyl ether Brij 56 (ICI) 13 PEG-20 cetyl ether Brij58 (ICI) 16 PEG-2 stearyl ether Brij 72 (ICI) 4.9 PEG-10 stearyl etherBrij 76 (ICI) 12 PEG-20 stearyl ether Brij 78 (ICI) 15 PEG-100 stearylether Brij 700 (ICI) >10

Ethers of polyethylene glycol and alkyl alcohols are suitablesurfactants for use in the present invention. Examples of thesesurfactants are shown here in Table 92.

TABLE 93 Sugar Esters Sugar Ester Surfactants Compound CommercialProduct (Supplier) HLB Sucrose distearate SUCRO ESTER 7 (Gattefosse), 3Crodesta F-10 (Croda) Sucrose distearate/ SUCRO ESTER 11 (Gattefosse),12 monostearate Crodesta F-110 (Croda) Sucrose dipalmitate 7.4 Sucrosemonostearate Crodesta F-160 (Croda) 15 Sucrose SUCRO ESTER 15(Gattefosse) >10 monopalmitate Sucrose monolaurate Saccharosemonolaurate 1695 15 (Mitsubishi-Kasei)

Esters of sugars are suitable surfactants for use in the presentinvention. Examples of such surfactants are shown here in Table 93.

TABLE 94 Polyethylene Glycol Alkyl Phenols Polyethylene Glycol AlkylPhenol Surfactants Compound Commercial Product (Supplier) HLB PEG-10-100Triton X series (Rohm & Haas), Igepal CA series >10 nonyl phenol (GAF,USA), Antarox CA series (GAF, UK) PEG-15-100 Triton N-series (Rohm &Haas), Igepal CO series >10 octyl phenol (GAF, USA), Antarox CO series(GAF, UK) ether

Several hydrophilic PEG-alkyl phenol surfactants are available, and aresuitable for use in the present invention. Examples of these surfactantsare shown here in Table 94.

TABLE 95 Polyoxyethylene-Polyoxypropylene Block Copolymers POE-POP BlockCopolymers a, b values in Compound HO(C₂H₄O)_(a) (C₃H₆O)_(b)(C₂H₄O)_(a)H HLB Poloxamer 105 a = 11 b = 16 8 Poloxamer 108 a = 46 b =16 >10 Poloxamer 122 a = 5 b = 21 3 Poloxamer 123 a = 7 b = 21 7Poloxamer 124 a = 11 b = 21 >7 Poloxamer 181 a = 3 b = 30 Poloxamer 182a = 8 b = 30 2 Poloxamer 183 a = 10 b = 30 Poloxamer 184 a = 13 b = 30Poloxamer 185 a = 19 b = 30 Poloxamer 188 a = 75 b = 30 29 Poloxamer 212a = 8 b = 35 Poloxamer 215 a = 24 b = 35 Poloxamer 217 a = 52 b = 35Poloxamer 231 a = 16 b = 39 Poloxamer 234 a = 22 b = 39 Poloxamer 235 a= 27 b = 39 Poloxamer 237 a = 62 b = 39 24 Poloxamer 238 a = 97 b = 39Poloxamer 282 a = 10 b = 47 Poloxamer 284 a = 21 b = 47 Poloxamer 288 a= 122 b = 47 >10 Poloxamer 331 a = 7 b = 54 0.5 Poloxamer 333 a = 20 b =54 Poloxamer 334 a = 31 b = 54 Poloxamer 335 a = 38 b = 54 Poloxamer 338a = 128 b = 54 Poloxamer 401 a = 6 b = 67 Poloxamer 402 a = 13 b = 67Poloxamer 403 a = 21 b = 67 Poloxamer 407 a = 98 b = 67

The POE-POP block copolymers are a unique class of polymericsurfactants. The unique structure of the surfactants, with hydrophilicPOE and lipophilic POP moieties in well-defined ratios and positions,provides a wide variety of surfactants suitable for use in the presentinvention. These surfactants are available under various trade names,including Synperonic PE series (ICI); Pluronic® series (BASF), Emkalyx,Lutrol (BASF), Supronic, Monolan, Pluracare, and Plurodac. The genericterm for these polymers is “poloxamer” (CAS 9003-11-6). These polymershave the formula:

HO(C₂H₄O)_(a)(C₃H₆O)_(b)(C₂H₄O)_(a)H

where “a” and “b” denote the number of polyoxyethylene andpolyoxypropylene units, respectively.

Examples of suitable surfactants of this class are shown here in Table95. Since the compounds are widely available, commercial sources are notlisted in the Table. The compounds are listed by generic name, with thecorresponding “a” and “b” values.

TABLE 96 Sorbitan Fatty Acid Esters Sorbitan Fatty Acid EsterSurfactants Compound Commercial Product (Supplier) HLB Sorbitanmonolaurate Span-20 (Atlas/ICI), Crill 1 (Croda), 8.6 Arlacel 20 (ICI)Sorbitan monopalmitate Span-40 (Atlas/ICI), Crill 2 (Croda), 6.7 NikkolSP-10 (Nikko) Sorbitan monooleate Span-80 (Atlas/ICI), Crill 4 (Croda),4.3 Crill 50 (Croda) Sorbitan monostearate Span-60 (Atlas/ICI), Crill 3(Croda), 4.7 Nikkol SS-10 (Nikko) Sorbitan trioleate Span-85(Atlas/ICI), Crill 45 (Croda), 4.3 Nikkol SO-30 (Nikko) Sorbitansesquioleate Arlacel-C (ICI), Crill 43 (Croda), 3.7 Nikkol SO-15 (Nikko)Sorbitan tristearate Span-65 (Atlas/ICI) Crill 35 (Croda), 2.1 NikkolSS-30 (Nikko) Sorbitan Crill 6 (Croda), Nikkol SI-10 (Nikko) 4.7monoisostearate Sorbitan sesquistearate Nikkol SS-15 (Nikko) 4.2

Sorbitan esters of fatty acids are suitable surfactants for use in thepresent invention. Examples of these surfactants are shown here in Table96.

TABLE 97 Lower Alcohol Fatty Acid Esters Lower Alcohol Fatty Acid EsterSurfactants Compound Commercial Product (Supplier) HLB Ethyl oleateCrodamol EO (Croda), <10 Nikkol EOO (Nikko) Isopropyl myristate CrodamolIPM (Croda) <10 Isopropyl palmitate Crodamol IPP (Croda) <10 Ethyllinoleate Nikkol VF-E (Nikko) <10 Isopropyl linoleate Nikkol VF-IP(Nikko) <10

Esters of lower alcohols (C₂ to C₄) and fatty acids (C₈ to C₁₈) aresuitable surfactants for use in the present invention. Examples of thesesurfactants are shown here in Table 97.

TABLE 98 Ionic Surfactants Ionic Surfactants Compound HLB FATTY ACIDSALTS >10 Sodium caproate Sodium caprylate Sodium caprate Sodium laurateSodium myristate Sodium myristolate Sodium palmitate Sodium palmitoleateSodium oleate 18 Sodium ricinoleate Sodium linoleate Sodium linolenateSodium stearate Sodium lauryl sulfate (dodecyl) 40 Sodium tetradecylsulfate Sodium lauryl sarcosinate Sodium dioctyl sulfosuccinate [sodiumdocusate (Cytec)] BILE SALTS >10 Sodium cholate Sodium taurocholateSodium glycocholate Sodium deoxycholate Sodium taurodeoxycholate Sodiumglycodeoxycholate Sodium ursodeoxycholate Sodium chenodeoxycholateSodium taurochenodeoxycholate Sodium glycol cheno deoxycholate Sodiumcholylsarcosinate Sodium N-methyl taurocholate Sodium lithocholatePHOSPHOLIPIDS Egg/Soy lecithin [Epikuron ™ (Lucas Meyer), Ovothin ™(Lucas Meyer)] Lyso egg/soy lecithin Hydroxylated lecithinLysophosphatidylcholine Cardiolipin Sphingomyelin PhosphatidylcholinePhosphatidyl ethanolamine Phosphatidic acid Phosphatidyl glycerolPhosphatidyl serine PHOSPHORIC ACID ESTERS Diethanolammoniumpolyoxyethylene-10 oleyl ether phosphate Esterification products offatty alcohols or fatty alcohol ethoxylates with phosphoric acid oranhydride CARBOXYLATES Ether carboxylates (by oxidation of terminal OHgroup of fatty alcohol ethoxylates) Succinylated monoglycerides [LAMEGINZE (Henkel)] Sodium stearyl fumarate Stearoyl propylene glycol hydrogensuccinate Mono/diacetylated tartaric acid esters of mono- anddiglycerides Citric acid esters of mono-, diglycerides Glyceryl-lactoesters of fatty acids (CFR ref. 172.852) Acyl lactylates: lactylicesters of fatty acids calcium/sodium stearoyl-2-lactylate calcium/sodium stearoyl lactylate Alginate salts Propylene glycol alginateSULFATES AND SULFONATES Ethoxylated alkyl sulfates Alkyl benzenesulfones α-olefin sulfonates Acyl isethionates Acyl taurates Alkylglyceryl ether sulfonates Octyl sulfosuccinate disodium Disodiumundecylenamideo-MEA-sulfosuccinate CATIONIC Surfactants >10 Lauroylcarnitine Palmitoyl carnitine Myristoyl carnitine Hexadecyl triammoniumbromide Decyl trimethyl ammonium bromide Cetyl trimethyl ammoniumbromide Dodecyl ammonium chloride Alkyl benzyldimethylammonium saltsDiisobutyl phenoxyethoxydimethyl benzylammonium salts Alkylpyridiniumsalts Betaines (trialkylglycine): Lauryl betaine (N-lauryl,N,N-dimethylglycine) Ethoxylated amines: Polyoxyethylene-15 coconut amine

Ionic surfactants, including cationic, anionic and zwitterionicsurfactants, are suitable hydrophilic surfactants for use in the presentinvention. Preferred anionic surfactants include fatty acid salts andbile salts. Preferred cationic surfactants include carnitines.Specifically, preferred ionic surfactants include sodium oleate, sodiumlauryl sulfate, sodium lauryl sarcosinate, sodium dioctylsulfosuccinate, sodium cholate, sodium taurocholate; lauroyl carnitine;palmitoyl carnitine; and myristoyl carnitine. Examples of suchsurfactants are shown here in Table 98. For simplicity, typicalcounterions are shown in the entries in the Table. It will beappreciated by one skilled in the art, however, that any bioacceptablecounterion can be used. For example, although the fatty acids are shownas sodium salts, other cation counterions can also be used, such asalkali metal cations or ammonium. Unlike typical non-ionic surfactants,these ionic surfactants are generally available as pure compounds,rather than commercial (proprietary) mixtures. Because these compoundsare readily available from a variety of commercial suppliers, such asAldrich, Sigma, and the like, commercial sources are not generallylisted in the Table.

The patent and non-patent references cited in this patent specificationare incorporated by reference in their entireties to the extent thattheir disclosures are not inconsistent with the explicit or implicitteachings of this application especially the definitions.

Embodiments of the invention include:

1. A composition suitable for administration to a subject in need oftreatment for a condition, comprising:

a pharmaceutically effective amount of bupropion hydrobromide salt,

wherein said bupropion hydrobromide composition is more stable than acorresponding composition comprising bupropion hydrochloride.

2. The composition of embodiment 1 wherein said composition is suitablefor oral administration to a subject in need of bupropionadministration.

3. The composition of embodiment 1 wherein said bupropion hydrobromidecomposition is more stable than an otherwise equivalent bupropionhydrochloride composition when stored for at least 3 months at 40degrees C. and 75% relative humidity.

4. The composition of embodiment 3 which is more stable when stored forat least 6 months at 40 degrees C. and 75% relative humidity.

5. The composition of embodiment 3 which contains less of at least onedegradation product characteristic of bupropion degradation after beingstored at 40 degrees C. at 75% relative humidity than an otherwisesimilar bupropion hydrochloride composition stored under the sameconditions.

6. The composition of embodiment 3 which exhibits less fluctuations inthe in vitro dissolution profile in at least one dissolution media thanan otherwise similar bupropion hydrochloride composition after beingstored for at least 3 months at 40 degrees C. and 75% relative humidity.

7. The composition of embodiment 1 which is coated with at least onecoating which prevents dose dumping when said composition is in 40%ethanol.

8. The composition of embodiment 7 which comprises a SMARTCOAT™.

9. The composition of embodiment 1 which comprises at least onepharmaceutically acceptable carrier or excipient.

10. The composition of embodiment 1 which is in the form of a tabletthat is bioequivalent to WELLBUTRIN™ OR ZYBAN™/WELLBUTRIN™ SR tabletswhen administered once daily to a subject in need thereof.

11. The composition of embodiment 10 which does not exhibit a foodeffect.

12. The composition of embodiment 10 which comprises 150, 174, 300 or348 mg of bupropion hydrobromide.

13. The composition of embodiment 1 which is suitable for administrationby topical means.

14. The composition of embodiment 1 which is suitable for transmucosalor transdermal delivery.

15. The composition of embodiment 1 which is suitable for injection.

16. The composition of embodiment 1 which is suitable for administrationby an inhalation route.

17. The composition of embodiment 1 wherein the bupropion containedtherein comprises at least 90% of one enantiomeric form of the bupropionsalt.

18. The composition of embodiment 1 wherein the bupropion containedcomprises at least 95-99% of one enantiomeric form of the bupropionsalt.

19. The composition of embodiment 1 wherein at least 90% of thebupropion contained therein comprises the (+) enantiomer.

20. The composition of embodiment 1 wherein at least 90% of thebupropion contained therein comprises the (−) enantiomer.

21. The composition of embodiment 1 wherein at least 95-99% of thebupropion comprises the (−) enantiomer.

22. The composition of embodiment 1 wherein at least 95-99% of thebupropion comprises the (+) enantiomer.

23. The composition of embodiment 1 which comprises at least one ofpolymorph I, polymorph II and polymorph III.

24. The composition of embodiment 23 which comprises polymorphs I, IIand III.

25. A substantially pure polymorph of bupropion hydrobromide.

26. The substantially pure polymorph of embodiment 25 which is polymorphI.

27. The substantially pure polymorph of embodiment 25 which is polymorphII.

28. The substantially pure polymorph of embodiment 25 which is polymorphIII.

29. The composition of embodiment 1 which is in a tablet formulation.

30. The composition of embodiment 1 which is in a capsule formulation.

31. The composition of embodiment 1 wherein said composition is anextended release formulation.

32. The composition of embodiment 1 wherein said composition is adelayed release formulation.

33. The composition of embodiment 1 which is an enhanced absorptionformulation.

34. The composition of embodiment 1 which is in a controlled releasematrix tablet formulation.

35. The composition of embodiment 1 which is an osmotic release deliverysystem.

36. The composition of embodiment 1 which is suitable for once-dailyadministration.

37. The composition of embodiment 1 which is suitable for twice-dailyadministration.

38. The composition of embodiment 28 which is bioequivalent to WELBUTRINER or ZYBAN™/WELLBUTRIN SR when administered once daily.

39. The composition of embodiment 1 which comprises from 50-400 mg ofbupropion.

40. The composition of embodiment 1 which comprises 150 or 174 mg ofbupropion.

41. The composition of embodiment 1 which comprises 300 or 48 mg ofbupropion.

42. The composition of embodiment 1 which comprises at least onefunctional or non-functional coating.

43. The composition of embodiment 42 wherein said coatings includemoisture barriers, control-release coats, enteric coats, coatings thataffect physical stability and/or coatings that affect the appearance ofthe composition.

44. The composition of embodiment 43 which comprises a moisture barrier.

45. The composition of embodiment 1 comprising a core that includes saidbupropion salt, a binder and a lubricant; and a control releasing coatsubstantially surrounding said core, wherein said composition providescontrolled release of said bupropion salt.

46. The composition of embodiment 45 which comprises at least oneadditional coating.

47. The composition of embodiment 45 wherein said additional coatingsinclude moisture barriers, enteric coats, control-release coats, coatsthat affect the physical stability of the composition and/or coatingsthat affect the physical appearance of the composition.

48. The composition of embodiment 47 wherein said additional coatssubstantially surround the core and/or the control-releasing coat.

49. The composition of embodiment 45 wherein said binder is polyvinylalcohol.

50. The composition of embodiment 45 which comprises a moisture barrieror enteric coat surrounding the core and/or control-releasing coat.

51. The composition of embodiment 45 wherein said lubricant is glycerylbehenate.

52. The composition of embodiment 45 wherein said control releasing coatincludes a water-insoluble polymer, a water-soluble polymer, andoptionally a plasticizer.

53. The composition of embodiment 52 wherein said water-insolublepolymer is ethylcellulose.

54. The composition of embodiment 52 wherein said water-soluble polymeris polyvinylpyrrolidone.

55. The composition of embodiment 52 wherein said plasticizer if presentcomprises a mixture of polyethylene glycol 4000 and dibutyl sebacate.

56. The composition of embodiment 52 wherein said control releasing coatincludes an aqueous dispersion of a neutral ester copolymer without anyfunctional groups, a polyglycol having a melting point greater thanabout 55° C., and one or more pharmaceutically acceptable excipients,wherein said coat is coated onto said core and cured at a temperature atleast equal to or greater than the melting point of the polyglycol.

57. The composition of embodiment 56 which comprises at least oneadditional coat.

58. The composition of embodiment 55 wherein said core is amicroparticle.

59. The composition of embodiment 55 wherein said core is an immediaterelease core.

60. The composition of embodiment 1 which additionally comprises asecond drug.

61. The composition of embodiment 60 wherein said second drug isselected from an anti-depressant, vasodilator, anti-anxiety agent,anti-inflammatory, anti-pain agent, anti-migraine agent,anti-drug-abuse, alcohol-abuse or nicotine abuse agent, anti-viralagent, sleep modulating agent, anti-mimetic, appetite depressant orenhancer, and neuropsychiatric agent.

62. The composition of embodiment 60 wherein the second drug is ananti-depressant.

63. The composition of embodiment 60 wherein the second drug isimmediately released upon administration.

64. The composition of embodiment 60 wherein the second drug does notcome into contact with the first drug in the composition.

65. The composition of embodiment 64 wherein the bupropion and seconddrug are comprised in different layers, portions of the composition ordifferent microparticles that are comprised in the composition.

66. The composition of embodiment 60 wherein said second drug iscitalopram.

67. The composition of embodiment 60 wherein said second drug isescitalopram.

68. The composition of embodiment 60 wherein the second drug isvenlafaxine.

69. A method of using a composition according to any one of embodiments1-68 for treatment in a subject in need of bupropion administration.

70. The method of embodiment 69 wherein said condition is selected fromthe group consisting of depression, addiction disorder, smokingcessation, obesity, and seasonal effective disorder.

71. The method of embodiment 69 wherein said condition is obesity.

72. The method of embodiment 69 wherein the condition is obesity.

73. The method of embodiment 69 wherein the condition is smokingcessation.

74. The method of embodiment 69 wherein the condition is seasonaleffective disorder.

75. A use of bupropion hydrobromide to prepare a medicament to treatconditions which benefit from administration of bupropion, wherein saidmedicament has greater stability than a corresponding medicamentcomprising bupropion hydrochloride.

76. The use of embodiment 75 wherein said greater stability results insaid bupropion hydrobromide medicament containing less of at least onemoiety characteristic of bupropion degradation than an otherwise similarbupropion hydrochloride composition when said compositions are bothstored for at least 3 months or at least 6 months at 40 degrees C. and75% relative humidity.

77. The use of embodiment 75 wherein said greater stability results insaid bupropion hydrobromide medicament exhibiting less fluctuation inthe in vitro dissolution profile in at least one dissolution mediumrelative to an otherwise similar bupropion hydrochloride compositionafter being stored for at least 3 months and/or 6 months at 40 degreesC. and 75% relative humidity.

78. The use of embodiment 75 wherein the medicament is a tablet.

79. The use of embodiment 75 wherein the medicament is a capsule.

80. The use of embodiment 75 wherein the medicament contains a seconddrug.

81. The use of embodiment 80 wherein the second drug is citalopram.

82. The use of embodiment 80 wherein the second drug is escitalopram.

83. The use of embodiment 80 wherein the second drug is venlafaxine.

We claim:
 1. A modified release osmotic dosage form comprising bupropionhydrobromide present in a therapeutically effective amount, wherein saiddosage form releases the bupropion hydrobromide by dispensing thebupropion hydrobromide from a core via at least one passageway in amembrane by pressure created in the core by osmosis and/or by theexpansion of a swellable material which forces the bupropionhydrobromide to be dispensed from the core of the dosage form.
 2. Themodified release osmotic dosage form according to claim 1, wherein saiddosage form exhibits an in-vitro release rate such that after 2 hoursfrom 0 to 20% by weight of the bupropion hydrobromide is released, after4 hours from 15% to 45% by weight of the bupropion hydrobromide isreleased, after 8 hours, from 40% to 90% by weight of the bupropionhydrobromide is released, and after 16 hours, more than 80% by weight ofthe bupropion hydrobromide is released.
 3. The modified release osmoticdosage form according to claim 1, wherein said core comprises bupropionhydrobromide and at least one osmagent.
 4. The modified release osmoticdosage form according to claim 3, wherein said at least one osmagent isselected from the group consisting of sodium chloride, calcium chloride,calcium lactate, sodium sulfate, lactose, glucose, sucrose, mannitol,urea, and mixtures thereof.
 5. The modified release osmotic dosage formaccording to claim 3, wherein said at least one osmagent is present inadmixture with said bupropion hydrobromide.
 6. The modified releaseosmotic dosage form according to claim 3, wherein said at least oneosmagent is present in a control releasing coat.
 7. A modified releaseosmotic dosage, wherein a core comprising bupropion hydrobromide issurrounded by a semipermeable membrane which permits entry of an aqueousliquid into the core and delivery of the bupropion hydrobromide from thecore to the exterior of the dosage form through at least one passagewayor by a combination of osmosis and diffusion such that the dosage formexhibits an in-vitro release rate such that after 2 hours no more than40% is released, after 4 hours 40-75% is released, after 8 hours atleast 75% is released and after 16 hours at least 85% is released. 8.The modified release osmotic dosage form according to claim 1, whereinsaid core comprises bupropion hydrobromide arranged in a layered,contacting arrangement with a swellable material to provide a core withtwo or more layers, which core is surrounded by a semipermeablemembrane.